Beruflich Dokumente
Kultur Dokumente
published by:
edited by: Peter PASmyth, UCD, Dublin Merck KGaA, Darmstadt, Germany
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 2 2009
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 p apers from
renowned international thyroid experts in order to pass
on the extensive experience which the a uthors possess
in their field to a wide r ange of physicians dealing with
H t Thyr idology
the diagnosis and therapy ofthyroid dis eases.
Responsible at M
erck KGaA, Darmstadt, Germany:
Sigrid Butz, M.D.
ETAs journal on hot and controversial topics
Free access:
Thyroid International 22009
erck KGaA, Darmstadt, Germany, D-64271 Darmstadt
M www.hotthyroidology.com
ISSN 0946-5464
Iodine Deficiency Disorders: Silent Pandemic 3
1. Introduction
Thyroid disorders are amongst the most prevalent of Autonomy can develop in nodular goitres leading occa-
medical conditions. Their manifestations vary consider- sionally to thyrotoxicosis and iodisation programmes
ably from area to area and are determined principally can also induce thyrotoxicosis, especially in those aged
by the availability of iodine in the diet. Epidemiological over 40 years with nodular goitres. Autoimmune thy-
studies of thyroid dysfunction have limitations, for roiditis or hypothyroidism has not been reported to
example the definition of overt hypothyroidism and complicate salt iodisation programmes. Little preva-
subclinical hypothyroidism, the selection criteria of the lence data exists for autoimmune thyroid disease in
sample used, the influence of age, sex, genetic and envi- areas of iodine deficiency.3
ronmental factors and the different techniques used for
the measurement of thyroid hormones and the relative In iodine-replete areas, most persons with thyroid
paucity of incidence data.1 disorders have autoimmune disease, ranging through
primary atrophic hypothyroidism, Hashimoto's thy-
Almost one-third of the world's population lives in areas roiditis to thyrotoxicosis caused by Graves' disease.
of iodine deficiency.2 In areas where the daily iodine Cross-sectional studies in Europe, the United States
intake is below 50g, goitre is usually endemic, and and Japan have determined the prevalence of hyper-
when the daily intake falls below 25g, hypothyroid- thyroidism and hypothyroidism and the frequency
ism is seen. The prevalence of goitre in areas of severe and distribution of thyroid autoantibodies in differ-
iodine deficiency can be as high as 80%. Populations at ent, mainly Caucasian, communities.1 Recent data
particular risk tend to be remote and live in mountain- from studies screening large population samples in
ous areas in South-East Asia, Latin America and Central the United States4,5 have revealed differences in the
Africa. Iodisation programmes are of proven value in frequency of thyroid dysfunction and serum thyroid
reducing goitre size and in preventing goitre develop- antibody concentrations in different ethnic groups,
ment and cretinism in children. Goitrogens in the diet, whereas studies from Europe have shown the influence
such as thiocyanate in incompletely cooked Cassava of dietary iodine intake on the epidemiology of thyroid
or thioglucosides in Brassica vegetables, can explain dysfunction.6 However studies of incidence of autoim-
some of the differences in prevalence of endemic goi- mune thyroid disease have only been conducted in a
tre in areas with similar degrees of iodine deficiency. small number of developed countries.7
2. Hypothyroidism
In persons living in iodine-replete areas, the cause of 2.1 Congenital hypothyroidism
acquired hypothyroidism is either chronic autoimmune Congenital hypothyroidism affects about one newborn
disease (atrophic autoimmune thyroiditis or goitrous in 3,500 to 4,000 births and is the most treatable cause
autoimmune thyroiditis [Hashimoto's thyroiditis]) or of mental retardation.1 There is an inverse relationship
destructive treatment for thyrotoxicosis, but this is between age at diagnosis and intelligence quotient
rarely discussed in the available studies. In iodine- (IQ) in later life. In iodine-replete areas, 85% of the
deficient countries a daily iodine intake below 25g, cases are due to sporadic developmental defects of the
particularly in preterm infants, is a more frequent thyroid gland (thyroid dysgenesis) such as the arrested
cause of hypothyroidism accounting for many cases in migration of the embryonic thyroid (ectopic thyroid)
Europe, Asia and Africa. or a complete absence of thyroid tissue (athyreosis).
The remaining 15% have thyroid dyshormonogenesis
defects transmitted by an autosomal recessive mode of
4 Thyroid International 2 2009
inheritance. Clinical diagnosis occurs in less than 5% of blacks than in other ethnic groups.5 Using a competi-
newborns with hypothyroidism because symptoms and tive immunoassay procedure, the reported prevalence of
signs are often minimal. As a result it is not possible to detectable TGAb and TPOAb levels were 10% and 12%
predict which infants are likely to be affected. Without of the healthy population. A hypoechoic ultrasound
prompt diagnosis and treatment most affected children pattern or an irregular echo pattern may precede TPOAb
gradually develop growth failure, irreversible mental positivity in autoimmune thyroid disease, and TPOAb
retardation and a variety of neuropsychological deficits. may not be detected in more than 20% of individuals
The value of screening for congenital hypothyroidism with ultrasound evidence of thyroid autoimmunity.9
in heel-prick blood specimens is unquestioned, and it
is now done routinely in many countries. 2.3 Prevalence of hypothyroidism
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)
The prevalence is higher in surveys of the elderly in the 26% had a value greater than 10mU/L. The percentage
community.1 The overall prevalence of hypothyroidism, of subjects with a high serum TSH concentration was
including those already taking T4, in Birmingham, UK, higher for women than men in each decade of age, and
of 1210 subjects aged 60 and over was 4% of women ranged from 4 to 21% in women and 3 to 16% in men.
and 0.8% of men aged over 60 years. In subjects aged An increase in serum TSH concentrations was also found
60 years or more in Framingham, 4% had serum TSH in men in the NHANES III study. In the same study serum
concentration greater than 10mU/L, of whom one-third TSH concentrations increased with age in both men and
had low serum T4 concentrations.7 Overt hypothyroid- women and were higher in whites than blacks, inde-
ism was found in 7% of 558 subjects aged between 85 pendent of serum antithyroid antibody concentrations.5
and 89 years in Leiden, Netherlands.12
Community studies of elderly persons have confirmed
2.4 Subclinical hypothyroidism the high prevalence of subclinical hypothyroidism in
this age group, with approximately 10% of subjects
The term subclinical hypothyroidism is used to describe over 60 years having serum TSH values above the nor-
the finding of a raised serum TSH but a normal FT4 in mal range.6,9 A further analysis of the NHANES III data
an asymptomatic patient. In the community, the most demonstrated that the 97.5 centile for those subjects
common aetiology is chronic autoimmune thyroiditis.1,9 aged over 80 was 7.49mU/L and 70% had a serum TSH
In the original Whickham survey, 8% of women (10% of greater than the population defined upper limit of the
women over 55 years of age) and 3% of men had sub- reference range of 4.5mU/L of whom only 40% were
clinical hypothyroidism.8 In the Colorado, USA, study, anti-thyroid antibody positive.13 Data from a US cohort
9.4% of the subjects had a high serum TSH concentra- aged 70 to 79 years found that black subjects had a
tion, of whom 9.0% had subclinical hypothyroidism.4 significantly lower prevalence of subclinical hypothy-
Among those with a high serum TSH concentration, roidism (2% in men, 3% in women), as compared with
74% had a value between 5.1mU/L and 10mU/L and white subjects (4% in men, 6% in women).14
6 Thyroid International 2 2009
In Pescopagano, there was a slightly lower prevalence ratios (with 95% CI) of developing spontaneous hypo-
of subclinical hypothyroidism (4% of women and 3% thyroidism in surviving women are shown in Table 2.
of men), but high serum antithyroid antibody concen- Either raised serum TSH or positive thyroid antibodies
trations were as prevalent, although at lower titres, as in alone or in combination are associated with a signifi-
iodine-replete communities. In Copenhagen (median
10 cantly increased risk of hypothyroidism. The odds are
urinary iodine excretion 70g/L), only 0.7% of subjects greatly increased when both risk factors are present
had subclinical hypo- and each had a similar
Table 2. D evelopment of spontaneous hypothyroidism in surviving
thyroidism, and 83% effect. The smaller
women and men at 20-year follow-up of Whickham survey:
of them had serum number of observed
odds ratios (with 95% CI)7
antithyroid antibody cases in men resulted
concentrations greater Women in wide but highly
than 200kU/L. Other TSH raised, regardless of thyroid antibody status
11 14 (924) significant confidence
studies of elderly per- Thyroid antibody + , regardless of TSH status 13 (819) limits but also did not
sons in iodine-deficient If thyroid antibody - , effect of raised TSH alone 8 (320) allow the independent
areas have suggested a If thyroid antibody + , additional effect of raised TSH 5 (211) effects of these risk
high prevalence of sub- If TSH normal, effect of thyroid antibody + alone 8 (515) factors to be calcu-
clinical hypothyroid- If TSH raised, additional effect of thyroid antibody + 5 (115) lated. In the surviving
ism with approximate- TSH raised and thyroid antibody + combined 38 (2265) women the annual risk
ly 10% of subjects over of spontaneous overt
60 years having serum Men hypothyroidism was
TSH values above TSH raised, regardless of thyroid antibody status 44 (19104) 4% in those who had
the normal range. Thyroid antibody + , regardless of TSH status 25 (1063) both high serum TSH
Subclinical hypothy- TSH raised and thyroid antibody + combined 173 (81-370) and antithyroid anti-
roidism is found at body concentrations,
higher frequency (18% in Iceland and 24% in Hungary) 3% if only their serum TSH concentrations was high,
in areas where iodine intake is high, but most cases are and 2% if only their serum thyroid antibody concentra-
not of autoimmune origin.1 tion was high; at the time of follow up the respective
rates of hypothyroidism were 55%, 33%, and 27%. The
2.5 Incidence of overt hypothyroidism probability of developing hypothyroidism was higher
in those women who had serum TSH concentrations
The 20 year follow up of the Whickham cohort pro- above 2.0mU/L and high serum titres of antithyroid
vided incidence data and allowed the determination microsomal antibodies during the first survey.
of risk factors for spontaneous hypothyroidism in this
period.15 The mean annual incidence of spontaneous The other incidence data for hypothyroidism are from
hypothyroidism in the surviving women during the short (and often small) follow-up studies.7 In elderly sub-
20 year follow up period was 3.5 per 1000 (95% con- jects, the annual incidence rate of hypothyroidism varies
fidence interval [CI] 2.8 to 4.5), increasing to 4.1 per widely between 0.2 and 7% in the available studies (see
1000 (95% CI 3.3 to 5.0) if all cases including those Table 1 and [1] for references). Data from the large popu-
who had received destructive treatment for thyrotoxi- lation study in Tayside, UK, has demonstrated that the
cosis were included. The mean annual incidence during standardised incidence of primary hypothyroidism varied
the 20-year follow-up period in men (all spontaneous between 3.90 and 4.89 per 1000 women per year between
except for one case of lithium-induced hypothyroidism) 1993 and 2001. The incidence of hypothyroidism in men
was 0.6 per 1000 (95% CI 0.3 to 1.2). The risk of having significantly increased from 0.65 to 1.01 per 1000 per year
developed hypothyroidism was examined with respect (P=0.0017). The mean age at diagnosis of primary hypo-
to risk factors identified in the first survey. The odds thyroidism decreased in women from 1994 to 2001.16,17
Iodine Deficiency Disorders: Silent Pandemic 7
Spontaneous recovery has also been described in sub- in patients with negative antithyroid antibodies and
jects with subclinical hypothyroidism, although the serum TSH levels less than 10mU/L, and within the first
frequency of this phenomenon is unclear. In one study, two years after diagnosis.9 However, all studies indicate
37% of patients normalised their serum TSH levels over that the higher the serum TSH value, the greater the
a mean follow-up time of 31.7 months. Normalisation likelihood of development of overt hypothyroidism in
of serum TSH concentrations were more likely to occur subjects with chronic autoimmune thyroiditis.
3. Hyperthyroidism
The most common causes of hyperthyroidism are Graves' 79 years in the US found evidence of hyperthyroidism
disease, followed by toxic multinodular goitre, whilst (defined biochemically as a serum TSH concentration
rarer causes include an autonomously functioning thy- less than 0.1mU/L and a serum free T4 concentration
roid adenoma, or thyroiditis. In epidemiological studies, greater than 23pmol/L in only five subjects (one man
however, the aetiology is rarely ascertained. and four women).14 In Leiden only 2 of 558 subjects
aged between 85 and 89 years had newly diagnosed overt
3.1 Prevalence of hyperthyroidism hyperthyroidism.12
The prevalence data in elderly persons show a wide The reported overall prevalence ranges from 0.5% to
range between 0.4% to 2.0%.1 A cross-sectional study 6.3%, with men and women over 65 years having the
of 2799 healthy community-dwelling adults aged 70 to highest prevalence; approximately half of them are tak-
8 Thyroid International 2 2009
ing thyroxine.1,9 Among these studies, the serum TSH but the age-specific incidence varies considerably (Table
cut-off value ranged from less than 0.1mU/L to less than 3 and [1] for references). The peak age-specific incidence
0.5mU/L and it is not clear how this difference affected of Graves disease was between 20 and 49 years in two
the reported prevalence rates. Among subjects with sub- studies, but increased with age in Iceland and peaked at
clinical hyperthyroidism, those with low but detectable 60 to 69 years in Malm, Sweden. The peak age-specific
serum TSH values may recover spontaneously when re- incidence of hyperthyroidism caused by toxic nodular
tested. In the Colorado study of 25,862 subjects (of whom goitre and autonomously functioning thyroid adenomas
88% were white), and in which the serum TSH cut-off in the Malm study was over 80 years. The only available
value was 0.3mU/L, the overall prevalence of subclinical data in a black population, from Johannesburg, South
hyperthyroidism was 2.1%.4 In contrast, the NHANES III Africa, also suggest a tenfold lower annual incidence of
study, defining subclinical hyperthyroidism using a more hyperthyroidism (0.09 per 1000 women and 0.007 per
stringent 0.1mU/L as the serum TSH cut-off, reported an 1000 men) than in whites.
overall prevalence of 0.7% in the total population and
0.2% in the thyroid disease-free population (n=13,344). In the survivors of the Whickham survey cohort, 11
The rates were highest in those subjects aged 20 to 39 women had been diagnosed and treated for hyperthy-
years and those more than age 79 years. In this study the roidism after the first survey and five women were
percentage of subjects with serum TSH concentrations diagnosed at the second survey.15 The aetiology in these
less than 0.4mU/L was significantly higher in women 16 new cases was Graves' disease in 10 subjects, multi-
than men, and black subjects had significantly lower nodular goitre in three subjects, an autonomously func-
mean serum TSH concentrations, and therefore a higher tioning thyroid adenoma in one, chronic autoimmune
prevalence of subclinical hyperthyroidism (0.4%) than thyroiditis in one and unknown in one. The mean annual
whites (0.1%) or Mexican Americans (0.3%). In the US incidence of hyperthyroidism in women was 0.8 per 1000
study of subjects aged 71 to 79 years the prevalence survivors (95% confidence interval [CI] 0.5 to 1.4).9 The
was 1.1% in women and 0.7% in men and there was no incidence rate was similar in the deceased women. No
difference between black and white residents.14 In the new cases were detected in men. Other cohort studies
Leiden study of subjects aged over 85 years, the preva- provide comparable incidence data, which suggests that
lence was 3%.12 many cases of hyperthyroidism remain undiagnosed in
the community unless routine testing is undertaken.1
The prevalence of subnormal serum TSH concentrations In the large population study in Tayside, Scotland, 620
(detection limit 0.01mU/L and excluding those subjects incident cases of hyperthyroidism were identified with an
taking thyroxine) was higher in the iodine-deficient incidence rate of 0.77/1000 per year (95% CI 0.70 to 0.84)
population of Pescopagano (6%), due to functional in women and 0.14/1000 per year (95% CI 0.12 to 0.18)
autonomy from nodular goitres.10 In Jutland, an area in men.16 The incidence increased with age, and women
of mild iodine deficiency in Denmark, 10% of a random were affected two to eight times more than men across
sample of 423 subjects had low serum TSH concentra- the age range. Recent further analysis suggested that the
tions, as compared with 1% of 100 subjects of similar age incidence of thyrotoxicosis was increasing in women but
in iodine-rich Iceland. Subclinical hyperthyroidism was not in men between 1997 and 2001.17
not detected in a group of elderly nursing home residents
in an iodine-rich region of Hungary.3 Data on the risk of progression of subclinical hyper-
thyroidism to overt hyperthyroidism are limited. In the
3.3 Incidence of hyperthyroidism majority of subjects a detectable below normal serum
TSH will eventually rise towards normal. In those sub-
The incidence data available for overt hyperthyroidism in jects with an undetectable serum TSH and a confirmed
men and women from large population studies are com- aetiology due to Graves disease or nodular disease, it
parable, at 0.4 per 1000 women and 0.1 per 1000 men, 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, UK8,15 2779 18+ T4, FT4I 0 4.7 20 years <0.1 0.8
(0.61.4)
Colorado, USA4 25,862 18+ TSH 1.0
NHANES III, USA5 16,533 12+ TSH, TT4 2.0
Pescopagano, Italy10 922 15+ TSH, FT4 20.0
Sapporo, Japan 4110 25+ TSH, TRAB* 2.7 5.1
Copenhagen, Denmark11 2656 4171 TSH, FT4 0 12.0
Memphis/Pittsburgh, USA14 2797 7079 TSH, FT4 0.7 2.8
Leiden, Netherlands12 599 8589 TSH, FT4 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+ T4 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, T4, T4 3 years 0.1 0.5
Iceland 230000 0+ T4, T4 3 years 0.1 0.4
Malm, Sweden 257764 0+ PBI 5 years 0.1 0.4
as to what constitutes a normal TSH, particularly in blinded interventional trial of thyroxine therapy for
older subjects. Although some subjects will progress subclinical hypothyroidism exists. No consensus exists
to overt hypothyroidism, recent data suggest a sig- regarding the treatment of subclinical hyperthyroidism
nificant proportion revert to normal without treatment. and any potential benefits of therapy must be weighed
Adopting a wait and see policy rather than interven- against the substantial morbidity associated with the
tion will avoid unnecessary treatment or the potential treatment of hyperthyroidism. There is an urgent need
for harm. Cardiovascular risk may be more significant for long-term studies of the effects of identification
in younger adults, approximately 1.5 versus 1.0 for and treatment of both subclinical hypothyroidism and
populations with mean ages younger or older than 65 subclinical hyperthyroidism, to determine if there is
years respectively.19 Treatment in subjects less than indeed benefit from screening for thyroid dysfunction
65 years and those older subjects with evidence of in adults.21
heart failure may now be justified.20 No appropriately
powered prospective, randomised, controlled, double-
Iodine Deficiency Disorders: Silent Pandemic 11
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12 Thyroid International 2 2009
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 g contains 25/50/75/88/100/112/125/137/150/175/200 g of levothyro
xine sodium. Other ingredients: Corn starch, croscarmellose sodium, gelatin, lactose monohydrate, magnesium stearate. Indications: Euthyrox 25 - 200 g: Euthyroid goitre, prophylaxis of relapse goitre after goitre resection, hypothyroidism,
suppression therapy in thyroid cancer. Additional indication for Euthyrox 25 - 100 g: Concomitant therapy in antithyroid drug therapy of hyperthyroidism after having achieved a euthyroid function. Additional indication for Euthyrox
100/150/200 g: 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.