Thyroid function John R Arthur* and Geoffrey J Beckett
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Thyroid function
John R Arthur* and Geoffrey J Beckett*
*Division of Micronutrient and Lipid Metabolism, Rowett Research Institute, Aberdeen, UK
f
University Department of Clinical Biochemistry, The Royal Infirmary, Edinburgh, UK
Normal thyroid status is dependent on the presence of many trace elements for
both the synthesis and metabolism of thyroid hormones. Iodine is most import-
ant as a component of the hormones, thyroxine and 3,3',5-tri-iodothyronine (T3)
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and iodine deficiency may affect approximately one billion people throughout
the world. Selenium is essential for normal thyroid hormone metabolism being
involved with selenium-containing iodothyronine de-iodinases that control the
synthesis and degradation of the biologically active thyroid hormone, T3.
Additionally, selenoperoxidases and thioredoxin reductase protect the thyroid
gland from peroxides produced during the synthesis of hormones. The roles of
iron, zinc and copper in the thyroid are less well defined but sub- or supra-
optimal dietary intakes of all these elements can adversely affect thyroid
hormone metabolism.
The importance of the thyroid gland in maintaining human health is
well recognised. Since iodine is a crucial constituent of thyroid hor-
mones, it is not surprising that thyroid dysfunction is very common in
geographical areas of iodine deficiency. However, even when this trace
element is present in adequate supply, thyroid disease is present in 3-5%
of the population. Furthermore, the regulated supply of thyroid
hormone to specific tissues is crucial during fetal development1.
There has been much research into thyroid gland biochemistry and
control, both under normal conditions and when thyroid hormone
metabolism is abnormal. Thyroid hormone metabolism and function is
a complex process and includes synthesis of the hormones and pro-
hormones in the thyroid gland, their inter-conversion by iodothyronine
de-iodinases in the organs of the body, and the binding of T3 to nuclear
receptors to control gene expression1. Thyroid hormone metabolism and
action are dependent on a multitude of enzymes and proteins and the
Correspondence to: expression or function of many of these can be influenced by trace
DrJR Arthur, elements.
Rowett Research The elements most closely associated with the thyroid are iodine and
Institute, Greenburn
Road, Bucksburn, selenium and their roles in thyroid hormone homeostasis are relatively
Aberdeen AB21 9SB. UKwell defined. In addition, levels of iron, zinc and copper in the diet have
British Medical Bulletin 1999; 55 (No. 3): 658-668 © The British Council 1999Trace elements and thyroid function
all been shown to influence thyroid metabolism, although the
mechanism of these effects is far from clear. This review will consider the
role of these trace elements in maintaining normal thyroid hormone
metabolism and in preventing dysfunction.
Thyroid disorders and iodine
Iodine is the trace element that is most likely to influence thyroid function
since it is an integral constituent of thyroid hormones. The recommended
daily requirement is 150-200 (ig. Iodine deficiency and its associated
clinical manifestations such as goitre, hypothyroidism, and impaired
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mental and physical development (cretinism) present a major world health
problem2. The most common thyroid disorders in areas of adequate
iodine intake are the autoimmune thyroid diseases and nodular goitre. In
these areas, hypothyroidism is commonly due to Hashimoto's thyroiditis
or results from atrophy of the gland (primary atrophic hypothyroidism).
Graves' disease, solitary nodular goitre, multinodular goitre and
autoimmune thyroiditis comprise the vast majority of patients who
present with an over active gland.
The effects of excess iodine intake
The increased use of iodine supplements in salt and bread and of iodine
containing food preservatives has resulted in a marked increase in iodine
intake in some countries including the US, Great Britain and Scandinavia.
This may be 4 times the recommended daily intake in certain regions and
there is now compelling evidence that such excess can give rise to thyroid
dysfunction3.
Following the acute administration of iodine, thyroid hormone pro-
duction is transiently inhibited (Wolff-Chaikoff effect). This effect has
been used clinically to render patients euthyroid prior to thyroid surgery,
by giving potassium iodide in combination with propranolol4. Indeed,
before the discovery of antithyroid drugs, patients with Graves' disease
were treated with high doses of iodide.
In areas that have been previously iodine deficient, iodine supplements
frequently give rise to hyperthyroidism which commonly manifests as
multinodular goitre. This has led to the suggestion that, in these patients,
there were pre-existing autonomous micronodules or macronodules but
that the hyperthyroidism was masked because of low iodine supply, only
to be uncovered when iodine was given3.
There is evidence, particularly in animals, that high levels of iodine can
be a contributing factor in the development of autoimmune thyroid
British Medical Bulletin 1999,55 (No. 3) 659Micronutrients in health and disease
disease. How iodine produces such an effect is unclear but it may involve
the production of iodine-rich thyroglobulin, which may be particularly
immunogenic. Some, but not all, studies in humans have shown that the
presence of serum anti-microsomal antibodies is more prevalent in areas
adequate in iodine than in areas of mild iodine deficiency3.
A role for iodine in modifying the effects of growth factors is also
possible. For example, epidermal growth factor receptors in thyrocytes
are greatly diminished in the presence of iodine.
The effects of low iodine intake
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Up to one billion people live in areas where they are at risk from the
effects of iodine deficiency. Of these, approximately 211 million have
goitre and about 20 million have impaired brain function. There are
many iodine deficiency diseases (IDDs) which can affect human subjects
of all ages, but they are particularly severe in fetal development and
during stages of rapid growth in infants giving rise to cretinism1.
The clinical outcomes of iodine deficiency thus range from mild hypo-
thyroidism to severe endemic cretinism. Cretinism manifests in two
quite different forms. In myxoedematous cretinism, there is severe
hypothyroidism and stunted growth but the prevalence of goitre is much
lower than that in non-cretins1. There is often thyroid atrophy with no
thyroid tissue being palpable. Typically plasma thyroxine (T4) and
3,3',5-tri-iodothyronine (T3) are very low whilst thyrotrophin (TSH) is
extremely high. Thyroid destruction in these subjects may start in utero
or soon after birth. In neurological cretinism, which is more common
than the myxoedematous form of the disease, mental deficiency may be
accompanied by neurological problems including hearing and speech
defects. Growth and thyroid function are usually normal.
Whilst the pathogenesis of cretinism is unclear, there is no doubt that
iodine deficiency plays the major role since the diseases may be
prevented by iodine supplementation of salt used for cooking by an
injection of iodised oil. However, other factors, which may vary with
geographical location, also influence the prevalence and type of the
disease. These may include goitrogens and selenium status1-5.
Selenium
Concentrations of selenium are higher in the thyroid than in any other
tissues other than liver and kidney, indicating that it has important
functions within the gland. In 1987, it became apparent that selenium
could exert marked effects on thyroid hormone metabolism in tissues
660 British Medical Bulletin 1999,55 (No 3)Trace elements and thyroid function
other than the thyroid6. It, therefore, differs in its action from iodine
whose effects on thyroid status are largely confined to the thyroid.
Selenium is an essential component of many selenoproteins that regulate
thyroid hormone synthesis, preserve thyroid integrity in conditions of
marked oxidative stress, and control hormone metabolism in non-
thyroidal tissues where the prohormone T, is converted to biologically
active T3 or its inactive isomer rT35"7.
Selenium and thyroid hormone de-iodination
The discovery of increased T4 and decreased T3 concentrations in plasma
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from selenium deficient rats and cattle provided the first demonstration
that selenium could affect thyroid hormone metabolism. These changes
were associated with considerable decreases in hepatic and renal type I
iodothyronine de-iodinase (IDI) activity which converts T4 to T3. These
observations led to the suggestion that IDI was a selenoenzyme; this was
subsequently proved by partial purification and cloning. The selenium
present as selenocysteine in IDI is coded for by a TGA stop codon5"7.
The levels of T4, T3 and rT3 are also regulated by two further de-
iodinases type II (IDII) and type HI (IDHI) that also contain selenium.
IDII shows quite a different tissue distribution from EDI and is found
principally in brain, central nervous system, brown adipose tissue and
the pituitary. The metabolic function of these tissues depends on T3
which is 'locally produced' from T4 by de-iodination catalysed by IDII.
This process provides a very sensitive mechanism by which thyroid
hormone metabolism can be finely regulated in specific tissues5'8.
To further refine the intracellular control of T3 at a tissue level, IDm
catalyses inner ring de-iodination, which converts T4 to the inactive rT3
and also catabolises T3 to produce the inactive T2 Thus co-ordinated
expression of the three de-iodinases can regulate the concentration of T3
that is presented to specific tissues5'8.
The ontogeny of the de-iodinases suggests that they are switched on
and off in utero and that this may be crucial in regulating and co-
ordinating fetal development in animals and humans. However, the
ontogeny of IDI in humans is quite different from that in the rat or the
sheep and thus data from animal models should be interpreted with
caution9.
Selenium deficiency and thyroid hormones
In selenium deficiency, there is a stria hierarchy of selenium supply to
specific tissues and also to different selenoenzymes within a tissue.
British Medial Bulletin 1999,55 (No. 3) 661Micronutrients in health and disease
Concentrations of selenium and selenoenzymes are greatly decreased in
liver, kidney and muscle, whereas those in the brain and endocrine
organs such as the thyroid gland are less affected. Indeed, the expression
of thyroidal IDI can even increase in selenium-deficient rats5. Within
different organs, specific selenoproteins are retained at the expense of
others, presumably to preserve the most important aspects of meta-
bolism in selenium deficiency10. For example, in the selenium-deficient
rat, EDI is better retained than cytoplasmic glutathione peroxidase in
thyroid, liver and kidney, presumably in order to preserve thyroid
function and iodothyronine de-iodination and to limit changes in
plasma T4, T3 and TSH5.
If selenium deficiency is continued over more than one generation in
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rats, plasma T4 concentrations may not be increased. The reasons for
this compensation are not fully understood but it may be that
homeostasis is achieved by increased metabolism of T4 by IDIIF.
Selenium, thyroid hormone synthesis and oxdidative damage in the thyroid
The functional unit for thyroid hormone synthesis is the follicle, a
structure made up of clusters of thyrocytes. These synthesise a high
molecular weight protein thyroglobulin, which is then exported and
stored as a colloid in the follicular lumen. Synthesis of thyroid hormones
requires iodination of tyrosyl residues on thyroglobulin and subsequent
coupling of these iodinated derivatives. These reactions take place within
the follicular lumen at the surface of the apical membrane and not within
the thyrocyte1-5.
Iodination of tyrosyl residues on thyroglobulin requires the generation
of hydrogen peroxide in high concentrations and also the action of
thyroid peroxidase, an enzyme located on the luminal side of the apical
membrane. The generation of H2O2 is probably crucial for the control
of thyroid hormone synthesis and is regulated by a complex network of
interacting second messenger systems. The thyrocyte is thus exposed to
high concentrations of H2O2 and consequently of toxic lipid hydro-
peroxides. However, the availability of H2O2 and the subsequent
peroxidative damage are decreased by selenoenzyme systems in the
thyrocytes which may be involved in regulating hormone synthesis.
Extracellular glutathione peroxidase is secreted by thyrocytes into the
follicular lumen and may regulate the availability of H2O2 for thyroid
peroxidase at the apical membrane11. The intracellular glutathione
peroxidases may detoxify H2O2 and lipid hydroperoxides within the
thyrocyte and protect the gland from oxidative damage. It is significant
that glutathione peroxidase activity is decreased by over 99% in the liver
but by only 50% in the thyroid of selenium-deficient rats10.
662 British Medical Bulletin 1999,55 (No. 3)Trace elements and thyroid function
Thioredoxin reductase may also protect against the damaging effects
of H2O2 in the thyrocyte. This selenoenzyme can also act a growth factor
and may have several important and diverse biological effects on the
cell, acting either directly or through thioredoxin. Signalling pathways
that are associated with increased H^C^ production, stimulate synthesis
of thioredoxin reductase in the thyrocyte. As well as having a potential
antioxidant role, thioredoxin reductase and thioredoxin can provide
reducing equivalents for the activity of IDI12.
It is less easy to demonstrate effects of selenium status on plasma TSH
and T3 concentrations in the heterogeneous human population. Never-
theless, low selenium status has been associated with changes in serum
thyroid hormone concentrations with an inverse correlation between
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plasma selenium and T4 concentrations consistent with low IDI activity
in low selenium status in elderly subjects. Moreover, selenium
supplementation decreased plasma T4, but plasma T3 and TSH con-
centrations were unaffected by selenium status and treatment13. Plasma
T4 concentrations are also elevated in subjects with phenylketonuria and
this has been attributed to low selenium status arising from
consumption of low protein diets. Selenium supplementation of these
patients decreased plasma T4 concentrations, consistent with an increase
in hepatic IDI activity14.
There is some evidence that de-iodination of thyroid hormones is
impaired in humans receiving large amounts of selenium, but this has
not been studied in detail15.
Selenium and the sick euthyroid syndrome
In euthyroid patients with severe illness not attributable to a thyroidal
cause (non-thyroidal illness: NTI), plasma concentrations of T3 are often
markedly decreased. This condition is very common in hospitalised
patients and is often referred to as the 'sick euthyroid' or 'low T3'
syndrome16. Such patients often also have decreased concentrations of
plasma selenium and this has led to the suggestion that the low T3 may
result from impaired expression of hepatic IDI17. Whilst selenium
supplementation can attenuate the fall in T3 in NTI, the syndrome has
complex effects which span the whole of the hypothalamic-pituitary
thyroid axis16-18. The hormone pattern in NTI is different from that in
simple selenium deficiency, where the most marked changes are in plasma
T4 not plasma T3. In contrast, in many patients with NTI, plasma T3
concentrations may be very low but with little change in plasma T416. The
fall in plasma selenium, which occurs in acute illness, may be a negative
acute phase response19.
British Medical Bulletin 1999;55 (No. 3) 663Micronutrients in health and disease
Combined selenium and iodine deficiencies
Several animal studies have been conducted to assess the effects of
combined selenium and iodine deficiencies. Selenium deficiency can
exacerbate the hypothyroidism and goitre due to iodine deficiency. In
contrast, selenium deficiency can increase or decrease brain IDII activity,
which is a crucial enzyme for the supply of T3 required for normal brain
development. Such animal studies illustrate the complex interactions
between selenium and iodine deficiency and provide some basis for
interpretation of the effects of the deficiencies in humans5.
The most comprehensive studies of the roles of selenium and iodine
deficiency in human thyroid metabolism have been carried out in Zaire
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in areas where there has been a high incidence of myxoedematous
cretinism. Cretinism was endemic in particular geological areas that
coincided with areas of low selenium soil content. This led to the
proposal that the thyroid atrophy was due to loss of protection from
toxic levels of hydrogen peroxide. In low selenium conditions the
thyrocyte was hypothesised to express less glutathione peroxidase and
hence to lose protection from the peroxidative stress generated by the
gland in iodine deficiency5'20-21.
Further support for this hypothesis has come from selenium supple-
mentation trials in the endemic goitre belt of Northern Zaire. Serum
selenium levels in children and cretins in this area were much lower than
levels in adults living in villages on the border of the endemia area and,
indeed, were similar to levels in severely selenium-deficient children in
China. When schoolchildren and cretins were given 50 ug Se/day (as
selenomethionine) for 2 months, serum selenium and red cell gluta-
thione peroxidase returned to normal. In the cretins, there was also a
marked fall in serum total T4 levels from an initial mean of 12.8 nmol/1
to 2.8 nmol/1, accompanied by a rise in TSH. These T4 concentrations
can be compared with a lower limit of normal of approximately 60
nmol/1 in many European countries. In the normal schoolchildren,
selenium supplementation also reduced serum T4 but without a con-
comitant rise in TSH concentrations5-20'21.
The fall in serum T4, which occurred, on giving selenium may have
resulted from an increase in the expression of hepatic IDI, which would
increase the metabolism of plasma T4 to T3. In the normal children with
adequate amounts of functional thyroid tissue, the gland would be able
to meet the subsequent increased requirement for T4 synthesis. However,
in cretins there was probably insufficient functional thyroid tissue to
meet the increased requirement for thyroid hormone5'20.
These studies led to the hypothesis that selenium deficiency may actually
protect the brain from some of the detrimental effects of iodine deficiency.
Since the brain depends on plasma T, for production of T3, which is
664 British Medial Bulletin 1999,55 (No. 3)Trace elements and thyroid function
essential for normal brain development, the increased plasma T4 con-
centrations in selenium deficiency may help to protect the fetal brain during
development. Thus it is now considered unethical to supplement a popul-
ation deficient in both selenium and iodine with selenium alone because of
the theoretical risk of exacerbating abnormal brain development20.
Selenium deficiency can not always totally explain the onset of endemic
cretinism in iodine-deficient areas. In certain provinces of Africa where the
degree of selenium deficiency is similar to that in Zaire but the iodine
deficiency is more severe, myxoedematous cretinism does not occur.
Similarly in areas of Tibet where iodine and selenium deficiencies are both
severe the incidence of myxoedematous cretinism is very low and
neurological cretinism predominates22. Thus, combined iodine and
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selenium deficiencies are not sufficient alone to explain the high frequency
of myxoedematous cretinism in Central Africa. The possible role of other
factors such as thiocyanates must again be considered.
The effects of thyroid disease on selenium status
Thyroid status appears to have an influence on selenium metabolism.
Patients with hyperthyroidism have lower levels of plasma selenium and
red cell glutathione peroxidase than do euthyroid subjects, regardless of
the cause of the hyperthyroidism. When treatment restores a euthyroid
state, these markers of selenium status also return to normal23. Low
selenium status is not the cause of the hyperthyroidism but rather the
hyperthyroidism diminishes the size of the plasma pool of selenium,
possibly by modifying the half-life of the selenoproteins.
Zinc and thyroid function
There are indications that zinc is also important for normal thyroid
homeostasis. Its roles are complex and may include effects on both the
synthesis and mode of action of the hormones. Thyroid hormone
binding transcription factors, which are essential for modulation of gene
expression, contain zinc bound to cysteine residues24. However, it is not
known whether dietary zinc deficiency has a direct effect on this aspect
of thyroid hormone metabolism. In cultured cells, very strong chelators
of zinc are required to influence binding of transcription factors to
DNA. In the thyroid gland itself, transcription factor 2, which interacts
with the promoters for the thyroglobulin and thyroperoxidase genes, is
a zinc-containing protein. The binding of transcription factor 2 is
affected by redox state, but again it is not known whether this can be
changed by dietary zinc intake24.
British Medical Bulletin 1999;55 (No. 3) 665Micronutrients in health and disease
The role of zinc in thyroid metabolism has been investigated in
animals but with conflicting results. Zinc deficiency can decrease plasma
T3 levels but in other studies no effect was observed. Similarly, zinc
deficiency has been reported to both increase and lower hepatic IDI
activity25*26. These conflicting reports may reflect differences in the
severity of the zinc deficiency and subsequent effects on food intake,
since this by itself would decrease plasma T3 levels and hepatic IDI
activity.
Marginal zinc deficiency appears to have no influence on the effects of
iodine deficiency in rats27. However, in a more complex study with
combined selenium, iodine and zinc deficiencies, there was an inter-
action between selenium and zinc deficiencies on thyroid follicle cell
architecture, which was compatible with apoptosis28.
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Zinc has also been connected with thyroid metabolism in humans.
Many patients with Down's syndrome have low serum zinc levels which
have been associated with diarrhoea and resultant malabsorption of
zinc. Those patients also had raised plasma TSH concentrations and
autoantibodies to thyroglobulin. When patients with Down's syndrome
were supplemented with zinc, plasma TSH levels were decreased to
normal and plasma reverse T3 was increased to normal29. In other
studies, low zinc status was associated with decreased thyroid hormone
levels. The biochemical basis of such changes has yet to be established30.
Other trace elements and the thyroid
Iron and copper status have also been linked to decreased plasma T3
concentrations in animals and man31'32. As with zinc, these changes have
not yet been associated with specific changes in enzymes involved in
thyroid hormone metabolism. It remains to be determined whether the
changes in thyroid metabolism are a direct result of the iron and copper
deficiencies or a non-specific response to poor health.
Acknowledgement
JRA is grateful to the Scottish Office Agriculture Environment and
Fisheries Department for financial support.
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