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2 I 2009 edited by: Peter PA Smyth, UCD, Dublin published by: Merck KGaA, Darmstadt,
2 I 2009 edited by: Peter PA Smyth, UCD, Dublin published by: Merck KGaA, Darmstadt,
2 I 2009
2 I 2009

edited by: Peter PA Smyth, UCD, Dublin

published by:

Merck KGaA, Darmstadt, Germany

UCD, Dublin published by: Merck KGaA, Darmstadt, Germany Epidemiology of Thyroid Dysfunction – Hypothyroidism and
UCD, Dublin published by: Merck KGaA, Darmstadt, Germany Epidemiology of Thyroid Dysfunction – Hypothyroidism and

Epidemiology of Thyroid Dysfunction – Hypothyroidism and Hyperthyroidism

Mark PJ Vanderpump

KGaA, Darmstadt, Germany Epidemiology of Thyroid Dysfunction – Hypothyroidism and Hyperthyroidism Mark PJ Vanderpump

Thyroid International

2

2009

Epidemiology of Thyroid Dysfunction – Hypothyroidism and Hyperthyroidism

Mark PJ Vanderpump Consultant Physician and Honorary Senior Lecturer in Endocrinology and Diabetes

Correspondence:

Mark PJ Vanderpump Department of Endocrinology Royal Free Hampstead NHS Trust Pond Street London NW3 2QG United Kingdom Tel: +44 207 4726280 Fax: +44 207 4726487 Email: mark.vanderpump@royalfree.nhs.uk

2 Thyroid International

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2009

Dr Mark Vanderpump has been a Consultant Physician and Honorary SeniorLecturerinDiabetes and Endocrinology at the Royal Free Hampstead NHS Trust in London since 1999. Having quali- fied at the University of Birmingham, his training was completed at posts in North East England and North Staffordshire. Whilst in Newcastle-upon-Tyne he was responsible for the 20-year follow-up of the Whickham survey. He has published on various aspects of thyroid disease and has been Secretary of the British Thyroid Association.

and has been Secretary of the British Thyroid Association. Thyroid International Editor-in-Chief: Peter PA Smyth, UCD,

Thyroid International

Editor-in-Chief: Peter PA Smyth, UCD, Dublin

This is the title of a publication series by Merck KGaA, Darmstadt, Germany. We are publishing papers from renowned international thyroid experts in order to pass on the extensive experience which the authors possess in their field to a wide range of physicians dealing with the diagnosis and therapy of thyroid diseases.

Responsible at Merck KGaA, Darmstadt, Germany:

Sigrid Butz, M.D.

Thyroid International · 2–2009

Merck KGaA, Darmstadt, Germany, D-64271 Darmstadt ISSN 0946-5464

Description of Picture for Front Page The famous Champions Statue, commemorating three of West Ham's play- ers who helped to win the 1966 World Cup for England. Captain Bobby Moore is held aloft with the cup. Geoff Hurst and Martin Peters, together with Ray Wilson (Fulham) are alongside him. It is located just outside Upton Park, the home ground of West Ham United Football Club in Newham, East London, near the site of the Olympic Stadium being built for 2012.

near the site of the Olympic Stadium being built for 2012. H t Thyr idology ETA’s
H t Thyr
H
t Thyr

idology

H t Thyr idology ETA’s journal on hot and controversial topics Free access: www. hotthyroidology.com

ETA’s journal on hot and controversial topics

Free access:

www. hotthyroidology.com

Iodine Deficiency Disorders: Silent Pandemic

3

1. Introduction

Thyroid disorders are amongst the most prevalent of medical conditions. Their manifestations vary consider- ably from area to area and are determined principally by the availability of iodine in the diet. Epidemiological studies of thyroid dysfunction have limitations, for example the definition of overt hypothyroidism and subclinical hypothyroidism, the selection criteria of the sample used, the influence of age, sex, genetic and envi- ronmental factors and the different techniques used for the measurement of thyroid hormones and the relative paucity of incidence data. 1

Almost one-third of the world's population lives in areas of iodine deficiency. 2 In areas where the daily iodine intake is below 50 μg, goitre is usually endemic, and when the daily intake falls below 25 μg, hypothyroid- ism is seen. The prevalence of goitre in areas of severe iodine deficiency can be as high as 80 %. Populations at particular risk tend to be remote and live in mountain- ous areas in South-East Asia, Latin America and Central Africa. Iodisation programmes are of proven value in reducing goitre size and in preventing goitre develop- ment and cretinism in children. Goitrogens in the diet, such as thiocyanate in incompletely cooked Cassava or thioglucosides in Brassica vegetables, can explain some of the differences in prevalence of endemic goi- tre in areas with similar degrees of iodine deficiency.

2. Hypothyroidism

In persons living in iodine-replete areas, the cause of acquired hypothyroidism is either chronic autoimmune disease (atrophic autoimmune thyroiditis or goitrous autoimmune thyroiditis [Hashimoto's thyroiditis]) or destructive treatment for thyrotoxicosis, but this is rarely discussed in the available studies. In iodine- deficient countries a daily iodine intake below 25 µg, particularly in preterm infants, is a more frequent cause of hypothyroidism accounting for many cases in Europe, Asia and Africa.

Autonomy can develop in nodular goitres leading occa- sionally to thyrotoxicosis and iodisation programmes can also induce thyrotoxicosis, especially in those aged over 40 years with nodular goitres. Autoimmune thy- roiditis or hypothyroidism has not been reported to complicate salt iodisation programmes. Little preva- lence data exists for autoimmune thyroid disease in areas of iodine deficiency. 3

In iodine-replete areas, most persons with thyroid disorders have autoimmune disease, ranging through primary atrophic hypothyroidism, Hashimoto's thy- roiditis to thyrotoxicosis caused by Graves' disease. Cross-sectional studies in Europe, the United States and Japan have determined the prevalence of hyper- thyroidism and hypothyroidism and the frequency and distribution of thyroid autoantibodies in differ- ent, mainly Caucasian, communities. 1 Recent data from studies screening large population samples in the United States 4,5 have revealed differences in the frequency of thyroid dysfunction and serum thyroid antibody concentrations in different ethnic groups, whereas studies from Europe have shown the influence of dietary iodine intake on the epidemiology of thyroid dysfunction. 6 However studies of incidence of autoim- mune thyroid disease have only been conducted in a small number of developed countries. 7

2.1 Congenital hypothyroidism Congenital hypothyroidism affects about one newborn in 3,500 to 4,000 births and is the most treatable cause of mental retardation. 1 There is an inverse relationship between age at diagnosis and intelligence quotient (IQ) in later life. In iodine-replete areas, 85 % of the cases are due to sporadic developmental defects of the thyroid gland (thyroid dysgenesis) such as the arrested migration of the embryonic thyroid (ectopic thyroid) or a complete absence of thyroid tissue (athyreosis). The remaining 15 % have thyroid dyshormonogenesis defects transmitted by an autosomal recessive mode of

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inheritance. Clinical diagnosis occurs in less than 5 % of newborns with hypothyroidism because symptoms and signs are often minimal. As a result it is not possible to predict which infants are likely to be affected. Without prompt diagnosis and treatment most affected children gradually develop growth failure, irreversible mental retardation and a variety of neuropsychological deficits. The value of screening for congenital hypothyroidism in heel-prick blood specimens is unquestioned, and it is now done routinely in many countries.

2.2 Asymptomatic autoimmune thyroiditis

The presence of high serum concentrations of thy- roid antibodies (anti-thyroid peroxidase [microsomal] [TPOAb] and anti-thyroglobulin [TGAb]) correlates with the presence of focal thyroiditis in thyroid tis- sue obtained by biopsy and at autopsy from patients with no evidence of hypothyroidism during life. Early post-mortem studies confirmed histological evidence of chronic autoimmune thyroiditis in 27 % of adult women, with a rise in frequency over 50 years, and 7 % of adult men, and diffuse changes in 5 % of women and 1 % of men. 1 Patients with hypothyroidism caused by either atrophic or goitrous autoimmune thyroiditis usually have high serum concentrations of these same antibodies. These antibodies also are often detected in serum of patients with Graves’ disease and other thyroid diseases, but the concentrations are usually lower.

There is considerable variation in the frequency and distribution of thyroid antibodies because of variations in techniques of detection, definition of abnormal titres, and inherent differences in the populations tested. In the UK Whickham survey, the mean serum TSH con- centrations were significantly higher in both men and women with positive serum antithyroid antibody tests, and 3 % of the subjects (5 % of women, 1 % of men) had both positive antibody tests and a serum TSH value greater than 6 mU/L. 8 In the Third National Health and Nutrition Examination Survey (NHANES III) in the USA, the percentage of subjects with high serum TPOAb and TGAb concentrations increased with age in both men and women, and high concentrations were more prevalent in women than in men and less prevalent in

blacks than in other ethnic groups. 5 Using a competi- tive immunoassay procedure, the reported prevalence of detectable TGAb and TPOAb levels were 10 % and 12 % of the healthy population. A hypoechoic ultrasound pattern or an irregular echo pattern may precede TPOAb positivity in autoimmune thyroid disease, and TPOAb may not be detected in more than 20 % of individuals with ultrasound evidence of thyroid autoimmunity. 9

2.3 Prevalence of hypothyroidism

In iodine-replete communities, the prevalence of spon- taneous hypothyroidism is between 1 % and 2 %, and it is more common in older women and ten times more common in women than in men. 1 In the Whickham survey, the prevalence of newly diagnosed overt hypo- thyroidism was 3 per 1000 women. 8 The prevalence of previously diagnosed and treated hypothyroidism was 14 per 1000 women, increasing to 19 per 1000 women when possible but unproven cases were included. The overall prevalence in men was less than 1 case per 1000. One third had been previously treated by surgery or radioiodine for thyrotoxicosis. Excluding iatrogenic causes, the prevalence of hypothyroidism was 10 per 1000 women, increasing to 15 per 1000 when pos- sible but unproven cases were included. The mean age at diagnosis was 57 years. Other studies in Northern Europe, Japan and the USA have found the prevalence to range between 0.6 and 12 per 1000 women and between 1.3 and 4.0 per 1000 in men investigated (see Table 1 and [1] for references). In the Colorado and NHANES III studies, the prevalence of newly diag- nosed hypothyroidism was 4 per 1000 and 3 per 1000 respectively. 4,5

In Pescopagano, Italy, an area of mild iodine deficiency (median urinary iodine excretion 55 μg/L), the preva- lence of newly diagnosed overt hypothyroidism was 0.3 % of 573 women (autoimmune thyroiditis confirmed as aetiology) (there were no cases among 419 men), and no subject had been diagnosed and treated for hypothy- roidism. 10 In borderline iodine-deficient Copenhagen, Denmark, 6 per 1000 of the women and 2 per 1000 men had overt but undiagnosed hypothyroidism, and 1 % of all subjects were taking thyroxine. 11

Iodine Deficiency Disorders: Silent Pandemic

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Table 1. Prevalence of previously undiagnosed overt hypothyroidism and incidence of overt hypothyroidism in selected epidemiological surveys of thyroid dysfunction (see reference 1 unless stated)

Study Name

N

Age (Years)

Test

Prevalence n/1000

 

Incidence n/1000/year

       

Men

Women

Follow-up

Men

Women

Whickham, UK 8,15

2779

18+

TSH, T4

0

3.3

20

years

0.6

3.5

 

(0.3–1.2)

(2.8–4.5)

Colorado, USA 4

25,862

18+

TSH

4.0

     

NHANES III, USA 5

16,533

12+

TSH

 

2.0

     

Pescopagano, Italy 10

992

15+

TSH, FT4

0

3.0

     

Sapporo, Japan

4110

25+

TSH

2.4

8.5

 

Copenhagen, Denmark 11

2656

41–71

TSH, FT4

2.0

5.0

     

Memphis/Pitttsburgh, USA 14

2797

70–79

TSH, FT4

5.4

13.0

     

Leiden, Netherlands 12

558

85–89

TSH, FT4

 

70

     

Tayside, UK (1993–1997) 16

390,000

0+

Treatment

4

years

0.88

4.98

for hypo-

 

(0.80–0.95)

(4.81–5.17)

thyroidism

Tayside, UK (1997-2001) 17

390,000

0+

As above

   

4

years

1.09

4.75

 

(0.95–1.25

(4.46–5.07)

Göteborg, Sweden

1283

44–66

TSH

6.4

4

years

1–2

Birmingham, UK

1210

60+

TSH

7.8

20.5

1 year

11.1

Gothenburg, Sweden

1148

70+

TSH

10

years

2

The prevalence is higher in surveys of the elderly in the community. 1 The overall prevalence of hypothyroidism, including those already taking T4, in Birmingham, UK, of 1210 subjects aged 60 and over was 4 % of women and 0.8 % of men aged over 60 years. In subjects aged 60 years or more in Framingham, 4 % had serum TSH concentration greater than 10 mU/L, of whom one-third had low serum T4 concentrations. 7 Overt hypothyroid- ism was found in 7 % of 558 subjects aged between 85 and 89 years in Leiden, Netherlands. 12

2.4 Subclinical hypothyroidism

The term subclinical hypothyroidism is used to describe the finding of a raised serum TSH but a normal FT4 in an asymptomatic patient. In the community, the most common aetiology is chronic autoimmune thyroiditis. 1,9 In the original Whickham survey, 8 % of women (10 % of women over 55 years of age) and 3 % of men had sub- clinical hypothyroidism. 8 In the Colorado, USA, study, 9.4 % of the subjects had a high serum TSH concentra- tion, of whom 9.0 % had subclinical hypothyroidism. 4 Among those with a high serum TSH concentration, 74 % had a value between 5.1 mU/L and 10 mU/L and

26 % had a value greater than 10 mU/L. The percentage of subjects with a high serum TSH concentration was higher for women than men in each decade of age, and ranged from 4 to 21% in women and 3 to 16% in men. An increase in serum TSH concentrations was also found in men in the NHANES III study. In the same study serum TSH concentrations increased with age in both men and women and were higher in whites than blacks, inde- pendent of serum antithyroid antibody concentrations. 5

Community studies of elderly persons have confirmed the high prevalence of subclinical hypothyroidism in this age group, with approximately 10 % of subjects over 60 years having serum TSH values above the nor- mal range. 6,9 A further analysis of the NHANES III data demonstrated that the 97.5 centile for those subjects aged over 80 was 7.49 mU/L and 70 % had a serum TSH greater than the population defined upper limit of the reference range of 4.5 mU/L of whom only 40 % were anti-thyroid antibody positive. 13 Data from a US cohort aged 70 to 79 years found that black subjects had a significantly lower prevalence of subclinical hypothy- roidism (2 % in men, 3 % in women), as compared with white subjects (4 % in men, 6 % in women). 14

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In Pescopagano, there was a slightly lower prevalence of subclinical hypothyroidism (4 % of women and 3 % of men), but high serum antithyroid antibody concen-

trations were as prevalent, although at lower titres, as in iodine-replete communities. 10 In Copenhagen (median urinary iodine excretion 70 μg/L), only 0.7 % of subjects had subclinical hypo-

thyroidism, and 83 % of them had serum antithyroid antibody concentrations greater than 200 kU/L. 11 Other studies of elderly per-

sons in iodine-deficient areas have suggested a high prevalence of sub- clinical hypothyroid- ism with approximate- ly 10 % of subjects over

60 years having serum

TSH values above the normal range. Subclinical hypothy-

roidism is found at higher frequency (18 % in Iceland and 24 % in Hungary) in areas where iodine intake is high, but most cases are not of autoimmune origin. 1

ratios (with 95 % CI) of developing spontaneous hypo- thyroidism in surviving women are shown in Table 2. Either raised serum TSH or positive thyroid antibodies

alone or in combination are associated with a signifi- cantly increased risk of hypothyroidism. The odds are greatly increased when both risk factors are present and each had a similar

effect. The smaller number of observed cases in men resulted in wide but highly

significant confidence

limits but also did not

allow the independent

effects of these risk

factors to be calcu-

lated. In the surviving women the annual risk of spontaneous overt hypothyroidism was 4 % in those who had

both high serum TSH and antithyroid anti-

body concentrations, 3 % if only their serum TSH concentrations was high, and 2 % if only their serum thyroid antibody concentra- tion was high; at the time of follow up the respective rates of hypothyroidism were 55 %, 33 %, and 27 %. The probability of developing hypothyroidism was higher in those women who had serum TSH concentrations above 2.0 mU/L and high serum titres of antithyroid microsomal antibodies during the first survey.

Table 2. Development of spontaneous hypothyroidism in surviving women and men at 20-year follow-up of Whickham survey:

odds ratios (with 95 % CI) 7

Women

TSH raised, regardless of thyroid antibody status

14

(9–24)

Thyroid antibody + , regardless of TSH status

13

(8–19)

If thyroid antibody - , effect of raised TSH alone

8

(3–20)

If thyroid antibody + , additional effect of raised TSH

5

(2–11)

If TSH normal, effect of thyroid antibody + alone

8

(5–15)

If TSH raised, additional effect of thyroid antibody +

5

(1–15)

TSH raised and thyroid antibody + combined

38 (22–65)

Men

TSH raised, regardless of thyroid antibody status

44

(19–104)

Thyroid antibody + , regardless of TSH status

25

(10–63)

TSH raised and thyroid antibody + combined

173 (81-370)

2.5 Incidence of overt hypothyroidism

The 20 year follow up of the Whickham cohort pro- vided incidence data and allowed the determination

of risk factors for spontaneous hypothyroidism in this period. 15 The mean annual incidence of spontaneous hypothyroidism in the surviving women during the

20 year follow up period was 3.5 per 1000 (95 % con-

fidence interval [CI] 2.8 to 4.5), increasing to 4.1 per 1000 (95 % CI 3.3 to 5.0) if all cases including those who had received destructive treatment for thyrotoxi- cosis were included. The mean annual incidence during the 20-year follow-up period in men (all spontaneous except for one case of lithium-induced hypothyroidism) was 0.6 per 1000 (95 % CI 0.3 to 1.2). The risk of having developed hypothyroidism was examined with respect to risk factors identified in the first survey. The odds

The other incidence data for hypothyroidism are from short (and often small) follow-up studies. 7 In elderly sub- jects, the annual incidence rate of hypothyroidism varies widely between 0.2 and 7 % in the available studies (see Table 1 and [1] for references). Data from the large popu- lation study in Tayside, UK, has demonstrated that the standardised incidence of primary hypothyroidism varied between 3.90 and 4.89 per 1000 women per year between 1993 and 2001. The incidence of hypothyroidism in men significantly increased from 0.65 to 1.01 per 1000 per year (P = 0.0017). The mean age at diagnosis of primary hypo- thyroidism decreased in women from 1994 to 2001. 16,17

Iodine Deficiency Disorders: Silent Pandemic

7

Spontaneous recovery has also been described in sub- jects with subclinical hypothyroidism, although the

frequency of this phenomenon is unclear. In one study,

37 % of patients normalised their serum TSH levels over

a mean follow-up time of 31.7 months. Normalisation

of serum TSH concentrations were more likely to occur

3. Hyperthyroidism

The most common causes of hyperthyroidism are Graves' disease, followed by toxic multinodular goitre, whilst rarer causes include an autonomously functioning thy- roid adenoma, or thyroiditis. In epidemiological studies, however, the aetiology is rarely ascertained.

3.1 Prevalence of hyperthyroidism

in patients with negative antithyroid antibodies and serum TSH levels less than 10 mU/L, and within the first two years after diagnosis. 9 However, all studies indicate that the higher the serum TSH value, the greater the likelihood of development of overt hypothyroidism in subjects with chronic autoimmune thyroiditis.

79 years in the US found evidence of hyperthyroidism (defined biochemically as a serum TSH concentration less than 0.1 mU/L and a serum free T4 concentration greater than 23 pmol/L in only five subjects (one man and four women). 14 In Leiden only 2 of 558 subjects aged between 85 and 89 years had newly diagnosed overt hyperthyroidism. 12

The prevalence of hyperthyroidism in women is between 0.5 and 2 %, and is ten times more common in women than in men in iodine-replete communities. In the Whickham survey, the prevalence of undiagnosed hyperthyroidism was 4.7 per 1000 women. 8 Hyperthyroidism had been previously diagnosed and treated in 20 per 1000 women, rising to 27 per 1000 women when possible but unproven cases were included, as compared with 1.6 to 2.3 per 1000 men, in whom no new cases were found at the survey.

disease, 2 per 1000 had “clinically significant” hyperthy-

The prevalence of undiagnosed hyperthyroidism in Pescopagano was higher, at 2 %, with a further 1 % of adults there having a history of toxic nodular goitre. 10 Approximately one-third had a diffuse goitre; the fre- quency in men and women was similar. In a population sample of 2656 from Copenhagen, another area of mild iodine deficiency, newly diagnosed thyrotoxicosis was found in 1.2 % of women and no men, and the prevalence of known thyrotoxicosis was 1.4 %. 11

The mean age at diagnosis was 48 years. Other available cross-sectional studies of the adult population provide

3.2 Subclinical hyperthyroidism

comparable data (see Table 3 and [1] for references). In NHANES III, in those subjects who were neither tak- ing thyroid medication nor reported histories of thyroid

roidism, defined as a serum TSH concentration less than 0.1 mU/L and a serum total T4 concentration greater than 170 nmol/L. 5 Overt hyperthyroidism, defined as serum TSH concentration less than 0.01 mU/L, was present in only 1 per 1000 of those not taking thyroid medication

Subclinical hyperthyroidism is defined as a low serum TSH concentration and normal serum T4 and T3 con- centrations, in the absence of hypothalamic or pituitary disease, non-thyroidal illness, or ingestion of drugs that inhibit TSH secretion such as glucocorticoids or dopa- mine. The available studies differ in the definition of a low serum TSH concentration and whether the subjects included were receiving thyroxine therapy. The third

in

the cross-sectional survey of 25,682 subjects aged over

generation assays have rarely been used in epidemiologi-

18

years attending the Health Fair in Colorado. 4

cal studies. 1

The prevalence data in elderly persons show a wide range between 0.4 % to 2.0 %. 1 A cross-sectional study of 2799 healthy community-dwelling adults aged 70 to

The reported overall prevalence ranges from 0.5 % to 6.3 %, with men and women over 65 years having the highest prevalence; approximately half of them are tak-

8 Thyroid International

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ing thyroxine. 1,9 Among these studies, the serum TSH cut-off value ranged from less than 0.1 mU/L to less than 0.5 mU/L and it is not clear how this difference affected the reported prevalence rates. Among subjects with sub- clinical hyperthyroidism, those with low but detectable serum TSH values may recover spontaneously when re- tested. In the Colorado study of 25,862 subjects (of whom 88 % were white), and in which the serum TSH cut-off value was 0.3 mU/L, the overall prevalence of subclinical hyperthyroidism was 2.1 %. 4 In contrast, the NHANES III study, defining subclinical hyperthyroidism using a more stringent 0.1 mU/L as the serum TSH cut-off, reported an overall prevalence of 0.7 % in the total population and 0.2 % in the thyroid disease-free population (n = 13,344). The rates were highest in those subjects aged 20 to 39 years and those more than age 79 years. In this study the percentage of subjects with serum TSH concentrations less than 0.4 mU/L was significantly higher in women than men, and black subjects had significantly lower mean serum TSH concentrations, and therefore a higher prevalence of subclinical hyperthyroidism (0.4 %) than whites (0.1 %) or Mexican Americans (0.3 %). In the US study of subjects aged 71 to 79 years the prevalence was 1.1 % in women and 0.7 % in men and there was no difference between black and white residents. 14 In the Leiden study of subjects aged over 85 years, the preva- lence was 3 %. 12

The prevalence of subnormal serum TSH concentrations (detection limit 0.01 mU/L and excluding those subjects taking thyroxine) was higher in the iodine-deficient population of Pescopagano (6 %), due to functional autonomy from nodular goitres. 10 In Jutland, an area of mild iodine deficiency in Denmark, 10 % of a random sample of 423 subjects had low serum TSH concentra- tions, as compared with 1 % of 100 subjects of similar age in iodine-rich Iceland. Subclinical hyperthyroidism was not detected in a group of elderly nursing home residents in an iodine-rich region of Hungary. 3

3.3 Incidence of hyperthyroidism

The incidence data available for overt hyperthyroidism in men and women from large population studies are com- parable, at 0.4 per 1000 women and 0.1 per 1000 men,

but the age-specific incidence varies considerably (Table

3 and [1] for references). The peak age-specific incidence of Graves’ disease was between 20 and 49 years in two studies, but increased with age in Iceland and peaked at

60 to 69 years in Malmö, Sweden. The peak age-specific

incidence of hyperthyroidism caused by toxic nodular goitre and autonomously functioning thyroid adenomas in the Malmö study was over 80 years. The only available data in a black population, from Johannesburg, South Africa, also suggest a tenfold lower annual incidence of hyperthyroidism (0.09 per 1000 women and 0.007 per 1000 men) than in whites.

In the survivors of the Whickham survey cohort, 11 women had been diagnosed and treated for hyperthy- roidism after the first survey and five women were

diagnosed at the second survey. 15 The aetiology in these

16 new cases was Graves' disease in 10 subjects, multi-

nodular goitre in three subjects, an autonomously func- tioning thyroid adenoma in one, chronic autoimmune thyroiditis in one and unknown in one. The mean annual incidence of hyperthyroidism in women was 0.8 per 1000 survivors (95 % confidence interval [CI] 0.5 to 1.4). 9 The incidence rate was similar in the deceased women. No new cases were detected in men. Other cohort studies provide comparable incidence data, which suggests that many cases of hyperthyroidism remain undiagnosed in the community unless routine testing is undertaken. 1 In the large population study in Tayside, Scotland, 620 incident cases of hyperthyroidism were identified with an incidence rate of 0.77/1000 per year (95 % CI 0.70 to 0.84) in women and 0.14/1000 per year (95 % CI 0.12 to 0.18) in men. 16 The incidence increased with age, and women were affected two to eight times more than men across the age range. Recent further analysis suggested that the incidence of thyrotoxicosis was increasing in women but not in men between 1997 and 2001. 17

Data on the risk of progression of subclinical hyper- thyroidism to overt hyperthyroidism are limited. In the majority of subjects a detectable below normal serum TSH will eventually rise towards normal. In those sub- jects with an undetectable serum TSH and a confirmed aetiology due to Graves’ disease or nodular disease, it has been calculated from short follow-up studies that the annual incidence is approximately 5 %. 1,9

Iodine Deficiency Disorders: Silent Pandemic

9

Table 3. Prevalence of previously undiagnosed overt hyperthyroidism and incidence of overt hyperthyroidism in selected epidemiological surveys of thyroid dysfunction (*TRAB = TSH receptor antibody, PBI =Protein-bound iodine, FT4I = Free thyroxine index). (See reference 1 unless stated)

Study Name

N

Age (Years)

Test

Prevalence n/1000

 

Incidence n/1000/year

       

Men

Women

Follow-up

Men

Women

Whickham, UK 8,15

2779

18+

T 4 , FT 4 I

0

4.7

20

years

<0.1

0.8

 

(0.6–1.4)

Colorado, USA 4

25,862

18+

TSH

 

1.0

     

NHANES III, USA 5

16,533

12+

TSH, TT 4

 

2.0

     

Pescopagano, Italy 10

922

15+

TSH, FT 4

20.0

     

Sapporo, Japan

4110

25+

TSH, TRAB*

2.7

5.1

 

Copenhagen, Denmark 11

2656

41–71

TSH, FT 4

0

12.0

     

Memphis/Pittsburgh, USA 14

2797

70–79

TSH, FT 4

0.7

2.8

     

Leiden, Netherlands 12

599

85–89

TSH, FT 4

4.0

     

Tayside, UK (1993-1997) 16

390,000

0+

Treatment

4

years

0.14

0.77

for hyper-

 

(0.11-0.22)

(0.70-0.84)

thyroidism

Tayside, UK (1997-2001) 17

390,000

0+

As above

4

years

0.15

0.91

 

(0.10-0.22)

(0.78-1.05)

Johannesburg, South Africa

?

0+

T

4

   

1

year

0.007

0.09

Birmingham, UK

1210

60+

TSH

0.9

1

year

0

1.5

Gothenburg, Sweden

1148

70+

TSH

10

years

1.0

Funen, Denmark

450000

0+

PBI, T 4 , T 4

3

years

0.1

0.5

Iceland

230000

0+

T 4 , T 4

3

years

0.1

0.4

Malmö, Sweden

257764

0+

PBI

5

years

0.1

0.4

4. Screening for thyroid disorders

Controversy exists as to whether healthy adults living in an area of iodine sufficiency benefit from screening for thyroid disease. It is desirable to detect any disease in its early stage, particularly when treatment is avail- able that will benefit the affected person and forestall or improve the natural history of the condition. The benefit from a screening programme must outweigh the physical and psychological harm caused by the test, diagnostic procedures and treatment. Thyroid disorders secondary to autoimmune thyroid disease are amongst the most prevalent of medical conditions, and their symptoms and signs may be subtle and non-specific and they can be mistakenly attributed to other illnesses, particularly in the elderly. The prevalence of unsus- pected overt thyroid disease is low, but a substantial proportion of subjects tested will have evidence of thyroid dysfunction, with approximately 10 % with subclinical hypothyroidism and 1 % with subclinical hyperthyroidism. In the absence of the confounding

effects of non-thyroidal illness or drugs, a normal serum TSH concentration has a high predictive value in ruling out thyroid disease in healthy subjects. In unselected populations, measurement of serum TSH has a sensitivity of 89 to 95 % and specificity of 90 to 96 % for overt thyroid dysfunction, as compared to cases confirmed by history, examination and addi- tional testing. Normal serum TSH concentrations are found in some patients with hypothyroidism caused by pituitary or hypothalamic disease, but both these situations are rare. In nearly all populations screened, a serum TSH value greater than 5 or 6 mU/L is accepted as being raised. 18

Different recommendations and position papers have been reported by various physician organisations as to whether subclinical thyroid disease is of sufficient clinical importance to warrant screening and therapy. In subclinical hypothyroidism, there is still debate

10 Thyroid International

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as to what constitutes a normal TSH, particularly in older subjects. Although some subjects will progress to overt hypothyroidism, recent data suggest a sig- nificant proportion revert to normal without treatment. Adopting a “wait and see” policy rather than interven- tion will avoid unnecessary treatment or the potential for harm. Cardiovascular risk may be more significant in younger adults, approximately 1.5 versus 1.0 for populations with mean ages younger or older than 65 years respectively. 19 Treatment in subjects less than 65 years and those older subjects with evidence of heart failure may now be justified. 20 No appropriately powered prospective, randomised, controlled, double-

blinded interventional trial of thyroxine therapy for subclinical hypothyroidism exists. No consensus exists regarding the treatment of subclinical hyperthyroidism and any potential benefits of therapy must be weighed against the substantial morbidity associated with the treatment of hyperthyroidism. There is an urgent need for long-term studies of the effects of identification and treatment of both subclinical hypothyroidism and subclinical hyperthyroidism, to determine if there is indeed benefit from screening for thyroid dysfunction in adults. 21

Iodine Deficiency Disorders: Silent Pandemic

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References

1. Vanderpump MPJ. The epidemiology of thyroid diseases. In: Braverman LE, Utiger RD, eds. Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text. 2005, 9th edn, pp 398-406. JB Lippincott-Raven, Philadelphia.

2. Zimmermann MB, Jooste PL, Pandav CS. Iodine-deficiency disorders. Lancet 2008; 372:1251-1262.

3. Laurberg P, Bulow Pedersen I, Knudsen N, Ovesen L, Andersen S. Environmental iodine intake affects the type of non-malignant thyroid disease. Thyroid 2001; 11:457-469.

4. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado Thyroid Disease Prevalence Study. Arch Intern Med 2000; 160:526-534.

5. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid antibodies in the United States popu- lation (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87:489-499.

6. Vanderpump MPJ, Tunbridge WMG. Epidemiology and prevention of clinical and subclinical hypothyroidism. Thyroid 2002; 12:839-847.

7. McGrogan A, Seaman HE, Wright JW, de Vries CS. The incidence of autoimmune thyroid disease: a systematic review of the literature. Clin Endocrinol 2008; 69:687-696.

8. Tunbridge WMG, Evered DC, Hall R, Appleton D, Brewis M, Clark F, Evans JG, Young E, Bird T, Smith PA.

The spectrum of thyroid disease in the community: the Whickham survey. Clin Endocrinol 1977; 7:481-493. 9. Biondi B, Cooper DC. The clinical significance of subclini- cal thyroid dysfunction. Endocr Rev 2008; 29:76-131

10. Aghini-Lombardi F, Antonangeli L, Martino E, Vitti P, Macherini D, Leoli F, Rago T, Grasse L, Valeriano R, Balestrieri A, Pinchera A. The spectrum of thyroid disor- ders in an iodine-deficient community: The Pescopagano Survey. J Clin Endocrinol Metab 1999; 84:561-566.

11. Knudsen N, Jørgensen T, Rasmussen S, Christiansen, Perrild H. The prevalence of thyroid dysfunction in a pop- ulation with borderline iodine deficiency. Clin Endocrinol 1999; 51:361-367.

12. Gussekloo J, van Exel E, de Craen AJM, Frölich M, Westendorp RGJ. Thyroid status, disability and cogni- tive function, and survival in old age. JAMA 2004;

292:2591-2599.

13. Surks MI, Hollowell JG. Age-specific distribution of serum thyrotrophin and anti-thyroid antibodies in the US population: implications for the prevalence of sub- clinical hypothyroidism. J Clin Endocrinol Metab 2007;

92:4575-4582.

14. Kanaya AM, Harris F, Volpato S, Pérez-Stable EJ, Harris T, Bauer D. Association between thyroid dysfunction and total cholesterol level in an older biracial population. The Health, Aging and Body Composition Study. Arch Intern Med 2002; 162:773-779.

15. Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, Young ET. The incidence of thyroid dis- orders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol 1995; 43:55-69.

16. Flynn RV, MacDonald TM, Morris AD, Jung RT, Leese GP. The Thyroid Epidemiology, Audit and Research Study; thyroid dysfunction in the general population. J Clin Endocrinol Metab 2004; 89:3879-3884.

17. Leese GP, Flynn RV, Jung RT, MacDonald TM, Murphy MJ, Morris AD. Increasing prevalence and incidence of thyroid disease in Tayside, Scotland: The Thyroid Epidemiology, Audit and Research Study (TEARS). Clin Endocrinol 2008; 68:311-316.

18. Tunbridge WMG, Vanderpump MPJ. Population screen- ing for autoimmune thyroid disease. Endocrinol Metab Clin North Am 2000; 29:239-253.

19. Razvi S, Shakoor A, Vanderpump M, Weaver J, Pearce S. The influence of age on the relationship between subclini- cal hypothyroidism and ischemic heart disease: A meta- analysis. J Clin Endocrinol Metab 2008; 93:2998-3007.

20. Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, Fried LP, Ladenson PW, Vittinghoff E, Gottdiener JS, Newman AB. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health Study. J Am Coll Cardiol 2008; 52:1152-1159.

21. Surks MI, Ortiz E, Daniels GH et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004; 291:228-238.

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Former Editions of Thyroid International

No 1-2009 Report on the 33rd Annual Meeting of the European Thyroid Association (L.H. Duntas, P.P.A. Smyth)

No 4-2008 Thyroid autoimmunity and female infertility (Kris Poppe, Daniel Glinoer, Brigitte Velkeniers)

No 3-2008 New reference range for TSH? (Georg Brabant)

No 2-2008 American Thyroid Association: Highlights of the 78th Annual Meeting (Stephen W Spaulding, Peter PA Smyth)

No 1-2008 Report of the 32th Annual Meeting of the European Thyroid Association (GJ Kahaly, P.P.A. Smyth)

No 4-2007 The Thyroid and Twins (Pia Skov Hansen, Thomas Heiberg Brix, Laszlo Hegedüs)

No 3-2007 Clinical Aspects of Thyroid Disorders in the Elderly (Valentin Fadeyev)

No 2-2007 Report of the 31th Annual Meeting of the European Thyroid Association (John H Lazarus, Peter PA Smyth)

No 1-2007 The story of the ThyroMobil (F. Delange, C.J. Eastman, U. Hostalek, S. Butz, P.P.A. Smyth)

No 3-2006 Thyroid Peroxidase – Enzyme and Antigen (Barbara Czarnocka)

No 2-2006 Genetics of benign and malignant thyroid tumours (Dagmar Führer)

No 1-2006 Highlights of the 13th ITC (Sheue-yann Cheng, Peter PA Smyth)

No 4-2005 Thyroid Eye Disease:

Current Concepts and the EUGOGO Perspective (Gerasimos E Krassas, Wilmar M Wiersinga)

No 3-2005 Clinical Expression of Mutations in the TSH Receptor: TSH-R Disorders (Davide Calebiro, Luca Persani, Paolo Beck-Peccoz)

No 2-2005 Transient Hypothyroxinaemia and Preterm Infant Brain Development (Robert Hume, Fiona LR Williams, Theo J Visser)

No 1-2005 The Spectrum of Autoimmunity in Thyroid Disease (Anthony P. Weetman)

No 5-2004 Postpartum Thyroiditis: An Update (Kuvera E. Premawardhana, John H. Lazarus)

No 4-2004 Report of the 29th Annual Meeting of the European Thyroid Association (G. Hennemann)

No 3-2004 Autoimmune Thyroiditis And Pregnancy (Alex F. Muller, Arie Berghout)

No 2-2004 Report of the 75th Annual Meeting of the American Thyroid Association (G. Hennemann)

No 1-2004 Thyroid and Lipids: a Reappraisal (Leonidas H. Duntas)

No 5-2003 Use of Recombinant TSH in Thyroid Disease:

An Evidence-Based Review (Sara Tolaney M.D., Paul W. Ladenson M.D.)

No 4-2003 New Insights for Using Serum Thyroglobulin (Tg) Measurement for Managing Patients with Differentiated Thyroid Carcinomas (C.A. Spencer)

No 3-2003 The Significance of Thyroid Antibody Measurement in Clinical Practice (A. Pinchera, M. Marinò, E. Fiore)

No 2-2003 Etiology, diagnosis and treatment of Graves’ disease (A.P. Weetman)

No 1-2003 Report of the 74th Annual Meeting of the American Thyroid Association (G. Hennemann)

No 6-2002 Report of the 28th Annual Meeting of the European Thyroid Association (G. Hennemann)

No 5-2002 Iodine Deficiency in Europe anno 2002 (François M. Delange, MD, PhD)

No 4-2002 Thyroid Imaging in Nuclear Medicine (Dik J. Kwekkeboom, Eric P. Krenning)

No 3-2002 Congenital Hypothyroidism (Delbert A. Fisher)

No 2-2002 The Use of Fine Needle Aspiration Biopsy (FNAB) in Thyroid Disease (Antonino Belfiore)

No 1-2002 Report of the 73rd Annual Meeting of the American Thyroid Association (G. Hennemann)

No 6-2001 Report of the 27th Annual Meeting of the European Thyroid Association (G. Hennemann)

No 5-2001 Subclinical Hyperthyroidism (E.N. Pearce, L.E. Braverman)

No 4-2001 Thyroid hormone treatment – how and when? (A.D. Toft)

No 3-2001 Resistance to thyroid hormone (O. Bakker, W.M. Wiersinga)

No 1/2-2001 Report of the 12th International Thyroid Congress (G. Hennemann)

No 5-2000 Percutaneous ethanol injection therapy for thyroid diseases (Enio Martino)

No 4-2000 Inheritable forms of thyroid carcinoma (Martin Schlumberger)

No 3-2000 Multinodular goitre (Peter Laurberg)

No 2-2000 Drug effects on thyroid function (Jan R. Stockigt)

No 1-2000 Thyroid disease, menstrual function and fertility (Gerasimos E. Krassas)

No 6-1999 Report of the 27th Annual Meeting of the American Thyroid Association (G. Hennemann)

No 5-1999 Report of the 26th Annual Meeting of the European Thyroid Association (G. Hennemann)

No 4-1999 Report of the 8th Biannual Meeting of the Latin American Thyroid Society (LATS) (Geraldo Medeiros-Neto)

Thyroid International is also published on the website ThyroLink: www.thyrolink.com (Literature)

When the thyroid secretly steals life. Taking the offensive against hypothyroidism. With Euthyrox. • multiple

When the thyroid

secretly steals life.

Taking the offensive against hypothyroidism. With Euthyrox.

• multiple dosage strengths for precise dose titration

• galenic formulation with reliable unit conformity

• first levothyroxine preparation with a European and FDA approval

Other registered tradenames: Eutirox, Supratirox, Lévothyrox

Euthyrox ® Offensive against hypothyroidism.
Euthyrox ®
Offensive against hypothyroidism.

Active substance: Levothyroxine sodium. Prescription only medicine. Composition: Each tablet (round with cross score) of Euthyrox 25/50/75/88/100/112/125/137/150/175/200 µg contains 25/50/75/88/100/112/125/137/150/175/200 µg of levothyro- xine sodium. Other ingredients: Corn starch, croscarmellose sodium, gelatin, lactose monohydrate, magnesium stearate. Indications: Euthyrox 25 - 200 µg: Euthyroid goitre, prophylaxis of relapse goitre after goitre resection, hypothyroidism, suppression therapy in thyroid cancer. Additional indication for Euthyrox 25 - 100 µg: Concomitant therapy in antithyroid drug therapy of hyperthyroidism after having achieved a euthyroid function. Additional indication for Euthyrox 100/150/200 µg: Thyroid suppression test. Contraindications: Intolerance to the active substance or any of the excipients. Untreated adrenocortical insufficiency, untreated pituitary insufficiency, untreated hyperthyroidism. Do not initiate therapy in acute myocardial infarction, acute myocarditis, acute pancarditis. Adverse reactions: Adverse reactions are not to be expected under adequate therapy. In (individual) intolerance of the chosen dosage or overdosage (particularly if the dose is increased too quickly at the start of treatment): tachycardia, palpitations, cardiac arrhythmias, angina pectoris, headache, muscle weakness and cramps, sensation of heat, fever, vomiting, menstrual disorders, pseudotumor cerebri, tremor, restlessness, insomnia, hyperhidrosis, weight loss, and diarrhoea. In such cases reduce the daily dosage or interrupt treatment for several days. Allergic reactions may occur in the case of hypersensitivity. Other notes: Treatment with thyroid hormones should be continued consistently during pregnancy in particular. The thyroid hormone quantity secreted into breast milk during lactation is not sufficient to cause development of hyperthyroidism or suppression of TSH secretion in the infant. During pregnancy contraindicated as concomitant treatment to antithyroid drug therapy. Exclude or treat coronary insufficiency, angina pectoris, arteriosclerosis, hypertension, pituitary or adrenocortical insufficiency, and thyroid autonomy before initiating therapy with thyroid hormones. Prevent drug-induced hyperthyroidism in coronary insufficiency, heart failure, and achycardiac arrhythmias. Clarify cause of secondary hypothyroidism before initiating replacement therapy. In compensated adrenocortical insufficiency start adequate replacement therapy where necessary. When hypothyroid, postmenopausal women at increased risk of developing oste- oporosis are treated, their thyroid function should be checked more frequently in order to prevent supraphysiologic levothyroxine blood levels. Do not use in: patients with galactose intolerance, lactase deficiency or glucose-galactose- malabsorption. Presentation and pack sizes: depending on the local registration state. For more detailed information please refer to the data sheet or package leaflet. Issued: August 2007. Merck KGaA, D-64271 Darmstadt, Germany.

please refer to the data sheet or package leaflet. Issued: August 2007. Merck KGaA, D-64271 Darmstadt,