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Article type: Systematic Review
Title: Micronutrient status, iodine nutrition and thyroid function: A systematic review.
Author names: S Maria O’Kane, Maria S Mulhern, L Kirsty Pourshahidi, JJ Strain and
Alison J Yeates
Author affiliations: Northern Ireland Centre for Food and Health (NICHE), School of
Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, Co. Londonderry,
BT52 1SA, UK
Corresponding author: Dr Alison Yeates, Room W2065, Northern Ireland Centre for Food
& Health (NICHE), School of Biomedical Sciences, University of Ulster, Cromore Road,
Coleraine, Co. Londonderry, BT52 1SA, UK
Email: a.yeates@ulster.ac.uk
Tel: +44 (0) 28 7012 3147
Fax Number: +44 (0) 28 7012 4965
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Abstract: 170 word limit
The thyroid gland is recognised for its role in maintaining human health. Thyroid hormone
metabolism is dependent on many proteins and enzymes. Iodine is a key component of
thyroid hormone biosynthesis while several other micronutrients are involved in maintaining
thyroid function and include selenium, zinc, iron and vitamin A. This systematic review
aimed to investigate the effect of micronutrient status and supplementation on iodine status
and thyroid hormone concentrations.
Electronic databases were searched from their inception to April 2016. Human studies
published in English which reported data on micronutrient status and iodine status and/or
thyroid hormone concentrations were included. Studies which examined the effect of
micronutrient supplementation on thyroid hormone concentrations and/or iodine status were
also included.
Although observational evidence suggests that status of selenium, zinc and iron are positively
associated with iodine status, data from randomised controlled trials fails to confirm this
relationship. Conclusions on the effect of micronutrient supplementation on iodine and
thyroid hormone status were hindered by the lack of studies and the heterogeneity in study
designs.
Keywords:
Micronutrient; iodine; nutrition; thyroid function
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Introduction
The thyroid gland is recognised for its role in maintaining human health through the
regulation of normal growth and metabolism.1,2 The thyroid hormones synthesised by the
thyroid, thyroxine (T4) and triiodothyronine (T3), are important for brain and neurological
development.1,3 Iodine is an essential component of these hormones and is therefore required
for their synthesis.1,4 Globally, it has been estimated that two billion people (31%) are iodine
deficient5 and that such deficiency is not confined to developing countries. Indeed, recent
epidemiological evidence has reported that 52% of the European population is iodine
deficient.5,6
Urinary iodine concentration (UIC) is a validated biomarker used to assess the risk of iodine
deficiency in a population.7 UIC is also a sensitive indicator of recent iodine intake and,
although it does not provide direct information on thyroid function, it can be used to indicate
the risk of thyroid dysfunction in a population.6,8 There is currently no consensus on the most
appropriate measure of iodine status at the individual level. However the urinary iodine to
creatinine ratio is often calculated as it corrects for urine volume.9 Thyroid hormone
concentrations (total and free triiodothyronine (T3) and thyroxine (T4), T3:T4 ratio) and
thyroglobulin (Tg) are also frequently used as indirect measures of iodine status. Serum
concentrations of thyroid hormones are tightly regulated by thyrotropin from the pituitary
gland10 and are maintained within relatively narrow limits, owing to this tight homeostatic
regulation.11 Evidence suggests that thyroid hormone concentrations (Thyroid stimulating
hormone (TSH), T3 and T4) will remain within normal ranges in mild iodine deficiency and
it is only in the case of severe iodine deficiency that results will fall outside the normal
ranges; thus limiting the sensitivity of thyroid hormones as a measure of iodine status.8,12,13
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Thyroid hormone metabolism is dependent on many proteins and enzymes and the expression
and function of these enzymes is influenced by the availability of iodine (Arthur & Beckett,
1999). In healthy adults, the body will contain 15–20mg of iodine, of which approximately
70–80% is present in the thyroid gland (Fisher & Oddie, 1969). In order to maintain normal
thyroid function, it is recommended that the minimum daily iodine intake for adults is 150µg
(EFSA, 2014) and of this 50-70µg/day is required to ensure an adequate supply of thyroid
hormones (de Groot, 1966; Stanbury, 1987; Zimmermann 2009a). Iodine is a key component
of thyroid hormone biosynthesis. Ingested iodide is absorbed in the small intestine and
transported in plasma to the thyroid gland where it is trapped, oxidised and binds to tyrosine
to form iodotyrosines in thyroglobulin (Tg) (Miot et al, 2000). Tg then undergoes proteolysis
and T3 and T4 hormones are secreted and transported to target tissues (Miot et al, 2000). The
thyroid adapts to low dietary iodine intakes (<100µg/day) by increasing thyroidal iodine
clearance and decreasing renal iodine clearance (Delange, 2000; Zimmermann 2009a). At
very low iodine intakes (<50µg/day), thyroidal iodine stores become depleted and many
individuals will develop goitre; an enlargement of the thyroid gland (Delange, 2000;
Zimmermann 2009a).
Several other micronutrients are involved in maintaining thyroid function and include
selenium, zinc, iron and vitamin A. Selenium is a necessary component of several
selenoproteins that play a role in the regulation of thyroid hormone synthesis and also protect
the thyroid gland from oxidative stress (Beckett & Arthur, 1994; Arthur et al, 1999). An
important function of selenium is the interaction it has with iodine in the conversion of the T4
hormone to the metabolically active T3 hormone (Beckett et al, 1987). In selenium
deficiency there is a hierarchy of selenium supply to specific tissues and while selenium
concentrations in the liver and kidney are decreased there appears to be less of an effect on
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the thyroid gland (Arthur & Beckett, 1999). Some evidence has shown altered thyroid
hormone levels in selenium deficient individuals and a reduced turnover of thyroid hormones
but the evidence is conflicting (Arthur & Beckett, 1999; Schomberg & Köhrle, 2008).
Previous animal and human studies have reported that iron is required for the initial stages of
thyroid hormone synthesis as thyroid peroxidase which is haem-dependent is required to
catalyse thyroid hormone synthesis (Zimmermann & Köhrle, 2002). Iron deficiency impairs
thyroid hormone metabolism as there is reduced thyroid peroxidase activity, decreased
conversion of T4 to T3 and significantly lower levels of circulating T3 and T4 (Dillman et al,
1979; Beard et al, 1990).
The role of vitamin A, zinc and copper in thyroid hormone metabolism has also been reported
(Drill, 1943; Dabbaghmanesh et al, 2007; Kazi et al, 2010a). Vitamin A is required for
adequate iodine uptake by the thyroid (Drill, 1943; Wolf, 2002) and previous research has
outlined how vitamin A deficiency can impair the synthesis of thyroglobulin and reduce
thyroidal iodine uptake (Strum, 1979; Oba & Kimura, 1980). Zinc is required for normal
thyroid homeostasis and the maintenance of thyroid function (Arthur & Beckett, 1999). In
addition to selenium, zinc is also involved in the conversion of the T4 to the metabolically
active T3 hormone (Chen et al, 1998). Copper is required for the synthesis of phospholipids
which stimulate TSH and copper deficiency has been shown to decrease thyroid hormone
concentrations (Aihara et al, 1984; Olin et al, 1994; Arthur & Beckett, 1999).
Micronutrient deficiencies often co-exist and can impair physical growth, brain and
neurological development and increase the risk of morbidity and mortality.26 Approximately
one third of the world’s population are deficient in one or more micronutrients, with iodine,
iron, zinc, vitamin A and folate being the most commonly reported micronutrient
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deficiencies.26 Such deficiencies in one or more of these essential vitamins or minerals are
typically a consequence of poor quality diets and/or inadequate micronutrient absorption as a
result of infection or inflammation.27 It is possible that micronutrient deficiencies may
contribute to altered thyroid function and exacerbate iodine deficiency.28
To date, no systematic review has studied the interactions between micronutrients, iodine
status and thyroid hormones. Given the high prevalence of iodine deficiency in Europe a
review of the evidence in this area is warranted. Therefore, the aim of this study was to
examine the evidence on the interaction between micronutrients, iodine status and thyroid
hormones. Within this, the specific objectives were to investigate the (1) associations
between micronutrient status and iodine and/or thyroid hormone concentrations, (2) the effect
of micronutrient supplementation on iodine and/or thyroid hormone concentrations. It was
hypothesised that there would be evidence of interactions between iodine and selenium, iron
and zinc and supplementation of these micronutrients would increase iodine status in iodine
deficient individuals.
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Methods
The present systematic review was conducted based on the Cochrane Systematic Review
Methodology29 and Preferred Reporting Items for Systematic Reviews and Meta-Analysis
(PRISMA) guidelines.30
Search strategy
Electronic databases (Medline OVID, EMBASE, Web of Science, PubMed and Cochrane
Library CENTRAL database) were searched from their inception up to April 2016 using text
terms with appropriate truncation and medical subject headings. A limit was placed on all
databases to search for human studies only. To check the sensitivity of the search in
identifying all potentially relevant papers, the search filter was tested in OVID Medline
(Supplementary Material). The search filter was modified as required for each database. A
secondary search of the reference lists of included studies was also completed to identify
additional potentially relevant articles.
Eligibility Criteria
Only full articles published in the English language were included. To be included, studies
must have measured and reported data for at least one of the following outcomes: UIC,
iodine: creatinine ratio, TSH, Tg, Total T3, Total T4, free T3 (FT3), or free T4 (FT4). Studies
conducted in children, adults, elderly adults and pregnant women were eligible for inclusion.
Observational studies were eligible for inclusion if they examined associations between
iodine and/or thyroid concentrations and micronutrients; concurrent iodine and micronutrient
deficiencies. Intervention studies were eligible for inclusion if they were a single nutrient
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supplementation study that investigated the effect(s) on iodine and/or thyroid hormone
concentrations; provided iodine supplementation and analysed the effect on micronutrient
status; or compared the effects of iodised salt to dual fortified salt (i.e. iron & iodised salt) on
iodine status or thyroid function. Intervention studies must have been for an adequate
duration to observe a change in nutrient status to be included, i.e. 6 weeks for selenium
(Ashton et al, 2009), 2 weeks for zinc (Lowe et al, 2009), 12 weeks for iron (Falkingham et
al, 2010) and 8 weeks for Vitamin A studies (Ramakrishnan et al, 2004). Intervention studies
or placebo-controlled trials carried out in areas with high rates of nutrient deficiencies are not
always feasible or ethical. For this reason, intervention studies were eligible for review if they
were: randomised controlled trials, non-randomised studies with a concurrent control group
and before-after studies. Intervention studies comparing dual-fortified salt with iodised salt
must have ensured that the iodine content of both salts was the same. Studies with
participants who had been diagnosed with thyroid disorders (i.e Grave’s disease), chronic
medical conditions (i.e. Hashimoto’s disorder, phenylketonuria), genetic conditions (i.e.
Down’s Syndrome) or consuming medication which might affect thyroid function were
excluded.
Study selection and data extraction
All search records returned from each database were exported to RefWorks™ and duplicate
records were removed. Titles and abstracts of potentially relevant articles were screened by
two reviewers using a pre-defined and piloted form (Supplementary Material) a joint decision
was made on the selection of studies meeting inclusion criteria and those not meeting the
inclusion criteria were removed. Disagreements regarding inclusion of ambiguous articles
were discussed with a third member of the research team and a consensus was agreed. Full
texts of the remaining articles were obtained and assessed for eligibility against the
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aforementioned criteria. For all included studies, a pre-designed and piloted data extraction
form was used to compile data from individual studies, including country/setting, sample
size, population group, study design, inclusion criteria and study findings (Supplementary
Material). Statistical data were also extracted where applicable.
Study quality and risk of bias
The Newcastle-Ottawa scale was used to assess the quality of cross-sectional.31 Risk of bias
was assessed for each intervention study included using Cochrane methodology.29
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Results
Study selection
Figure 1 presents a PRISMA flow chart detailing the selection of studies. Searches identified
15,007 references which were screened by abstract for eligibility. Of these 14,801 references
were removed as they did not meet the selection criteria. Subsequently, 206 full-text articles
were retrieved and assessed for eligibility. Of the 206 full-text articles retrieved, 149 did not
meet inclusion criteria and were excluded. Reasons for exclusion included missing data or a
study design or population group which did not meet inclusion criteria. In total, 57 studies
were included in this review. Twenty studies were intervention studies and 37 studies were
observational. Of the 20 intervention studies included in this review, 2 also assessed baseline
associations between iodine or thyroid hormones and nutrient status.32,33 In total, there were
37 cross-sectional and baseline observations from 2 intervention studies.
Characteristics of included studies
The characteristics of included studies are detailed in Supplementary Material Tables 1-2.
The 37 cross-sectional studies included within this review involved a total of 27,726
participants. The 20 included intervention studies involved a total of 4,136 participants.
Included studies were conducted in a range of population groups including children, adults,
elderly adults and pregnant women. The majority of studies included both males and females.
Studies had been conducted in many countries worldwide, in countries with and without salt
iodization and in both developed and developing countries.
Observational evidence of associations between UIC and micronutrient status
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Of the 10 studies that examined the association between selenium status and UIC, 8 reported
a positive association and of the 5 studies that examined the association between iron status
and UIC, 3 reported a positive association (Table 1). Only one study examined the
association between vitamin A status and UIC and reported no significant association.35 There
were 5 studies that examined the association between zinc status and UIC and 3 reported a
positive association. The discrepancy in reported study findings may result from measuring
different biomarkers of zinc status (urine vs. serum). Only one study examined associations
between copper status and iodine status and reported no significant association.36 There was
only one study which examined the association between molybdenum status and iodine
status, and this study reported a positive association.37
Observational evidence of associations between thyroid hormones and micronutrient status
The majority of studies reported no significant association between thyroid hormone indices
(TSH, T3 or T4) and selenium or iron status (Table 2). Of the 5 studies that examined the
association between selenium and the T3:T4 ratio, 3 reported a positive association while 2
reported no significant association. Only 2 studies examined the associations between vitamin
A status and thyroid hormone parameters; overall there does not seem to be any association
with thyroid hormones and vitamin A status.37,38 The majority of studies reported no
significant association between thyroid hormone indices and zinc status. Only 1 study
investigated the associations between copper status and thyroid hormone concentrations
(Table 2). This study reported positive associations between copper status and thyroid
hormone concentrations in female participants only.39 There were 2 studies that examined
associations between vitamin D status and thyroid hormone concentrations (Table 2). One
study found a negative association between vitamin D and TSH but only in participants aged
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15-44 years.40 No significant associations were reported from the other study investigating the
association between vitamin D and thyroid hormone concentrations.41
Effect of micronutrient supplementation on iodine and thyroid hormones
The effect of selenium supplementation on thyroid hormone concentrations was measured in
9 studies and 1 investigated the effect on UIC (Table 4). The majority of studies found that
selenium supplementation did not significantly affect iodine status or thyroid hormones. The
effect of iron supplementation on thyroid hormone concentrations was measured in 4 studies
and 5 intervention studies investigated the effect on iodine status. The majority of studies
found that iron supplementation did not significantly affect TSH, T3, T4 or iodine status.
One study found that vitamin A intervention decreased TSH and Tg in iodine deficient
participants while dual fortified salt (vitamin A and iodine) had minimal effects of thyroid
hormone concentrations.45 The other intervention study reported that vitamin A
supplementation decreased TSH and T4 concentrations while T3 concentrations increased
(Table 4).46 The effect of zinc supplementation on thyroid hormone concentrations was
measured in one study. This study reported that TSH was decreased while T3 and T4
concentrations increased in goitrous participants following zinc supplementation (Table 4).34
Co-existing deficiencies
Only 3 studies included in this review investigated the prevalence of iodine and co-existing
micronutrient deficiencies.36,47,48 These studies reported iodine deficiency or thyroid
dysfunction to commonly present with iron, zinc and vitamin A deficiencies.
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Quality of included studies
The majority of included cross-sectional studies scored highly for selection as shown in
Supplementary Material Table 3. Most studies selected participants randomly and they were
representative of the general population. All studies used a validated measurement tool
(biochemical analysis) to ascertain the exposure. The majority of studies were awarded only
one or no stars for comparability. The low quality was largely a result of studies that did not
control for important factors such as thyroid condition, age or sex. The majority of studies
were awarded 2-3 stars for the outcome category meaning that the appropriate statistical
analysis was conducted and was fully described.
Performance bias was low in 18 of the 20 included intervention studies (Supplementary
Material Table 4). This finding indicates that blinding of participants and personnel was
adequately described within the studies. In the majority of studies, baseline differences were
controlled for and the risk of other bias was considered to be low. Attrition bias was high in
four of the included studies. One of these studies stopped providing micronutrient
supplementation before the end of the study, two of these studies had endpoint data missing
and one study terminated early. Selection bias was described as unclear for many intervention
studies as little or no information was given on how participants were randomised to
intervention or control arms of the study. Detection bias was also classed as unclear in the
majority of studies. It was unclear if participants were aware of the study outcome or if they
were blinded. In a large number of studies, it was unclear if reporting bias was present; it was
unclear if a predefined protocol was available and only a few studies made reference to a
published study protocol.
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Discussion
This systematic review evaluated the evidence from observational and intervention studies on
the interaction between micronutrients, iodine status and thyroid hormones.
The majority of evidence presented in this review showed status of selenium, iron and zinc to
be positively associated with iodine status, as measured by UIC. The interaction of iodine and
selenium, iron and zinc is well recognised; selenium and zinc are required for the conversion
of the T4 hormone to the metabolically active T3 hormone (Beckett et al, 1987; Chen et al,
1998), while iron is required for the initial stages of thyroid hormone synthesis (Zimmermann
& Köhrle, 2002). It is important to recognise that in the presence of iodine deficiency,
particularly severe iodine deficiency, other micronutrient deficiencies may also exist. Iron,
selenium and zinc deficiencies often coexist with iodine deficiency and can impair thyroid
function. Deficiencies of iodine, selenium, iron and zinc share similar causal factors, namely
inadequate dietary intake, consumption of a predominantly plant-based diet and diseases that
either cause excessive nutrient losses or impair the absorption of micronutrients.2
Deficiencies of selenium, iron and zinc can blunt the effectiveness of iodine supplementation
programmes and should be corrected to maximise the efficacy of iodine supplementation
programmes.20,28 In areas of severe iodine and selenium deficiency, it is imperative that iodine
status is corrected and normalised before treatment for selenium deficiency is initiated to
prevent the onset of hypothyroidism (Zimmermann & Köhrle, 2002). Given the associations
between micronutrients and iodine outlined in the present review, it is important that health
professionals adopt a holistic approach in the treatment of micronutrient deficiencies as
altering the status of one micronutrient may have deleterious effects on iodine status and thus
thyroid function.
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Although there is evidence that vitamin A and copper have a role in thyroid function, the lack
of suitable observational studies made it difficult to draw any meaningful conclusions on the
associations between other micronutrients (vitamin A, copper and molybdenum) and iodine
status and further research is required in this area. Future research should also investigate if
other micronutrient deficiencies are present in the case of mild or moderate iodine deficiency.
There is a paucity of data on the co-existence of iodine and other micronutrient deficiencies
and the prevalence of micronutrient deficiencies should be monitored at a population level
particularly in groups vulnerable to the effects of these deficiencies such as pregnant women.
The association between iodine and micronutrients appears to be consistent across both
developing and developed countries and across a spectrum of countries with varying levels of
salt iodization legislation which proves interesting considering that the underlying
micronutrient status of these populations may be considerably different. Further research is
required to investigate the cause of iodine deficiency in developed countries and in particular
to establish if deficiencies in other micronutrients may be contributing to the prevalence of
iodine deficiency observed. Future studies should also investigate the effect of salt iodisation
programmes on micronutrient status.
Micronutrients including selenium, zinc, iron, copper and vitamin A are required for the
regulation and metabolism of thyroid hormones.1,28 Animal studies have demonstrated
associations between micronutrient status and thyroid hormones but it is much more difficult
to confirm these associations in heterogeneous human populations.1 The present review has
found that there is little evidence of an association between micronutrients and thyroid
hormones. Recent research has demonstrated that Tg is a sensitive marker of iodine status as
it is more sensitive to changes in dietary iodine intake in comparison to TSH, T3 and T4. 9,49
The majority of studies included in this review have not measured Tg and therefore the effect
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of micronutrient status and supplementation on Tg concentrations remains unknown and
research is required in this area.
Despite the relatively consistent observational evidence which shows a positive association
between selenium, iron, zinc and iodine, status only a limited number of intervention studies
have measured the effect of micronutrient supplementation on iodine status. The majority of
micronutrient supplementation trials included in this review have demonstrated no effect of
supplementation on thyroid hormones. Following micronutrient supplementation, thyroid
function may remain unchanged as concentrations of thyroid hormones in serum are tightly
regulated and are maintained within relatively narrow limits.10,11 Methodological differences
between studies are likely to have contributed to the inconsistency in reported findings. There
was considerable variation in the type of intervention delivered (whole diet vs.
supplementation) and the duration of supplementation (8 weeks to 5 years). Seasonality is
also known to influence thyroid function,51 yet many of the studies included in the current
review did not report nor controlled for season in their study design or analyses. Included
intervention studies have been conducted in populations with varying levels of iodine and
micronutrient deficiencies which may affect the response to micronutrient
supplementation.20,28 Thyroid function is known to decline with age,52,53 yet several of the
included intervention studies were conducted in elderly populations; this makes it difficult to
compare results with younger populations.
The comparability between intervention studies is also limited by analytical differences in the
method of nutrient assessment used and differences in the time of day of blood collections
which can affect thyroid hormone results.54 Many of the studies included in this review were
not intended to assess the effect of micronutrient supplementation on iodine and thyroid
hormones as a primary outcome. Future randomised controlled trials intervening with iodine
should measure the effect on status of other micronutrients in particular selenium, iron and
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zinc. There are a number of factors including age, ethnicity, sex and body mass index (BMI)
which can influence thyroid function,52,53,55,56 and should be taken into account when
designing and interpreting research studies. Although there is potentially large heterogeneity
between studies in terms of design and population groups, the majority of included studies
are of high quality. A limitation of the present review is that due to limited resources, only
papers published in the English language were eligible for inclusion.
Iodine is a key nutrient consideration for women of childbearing age and those planning a
pregnancy.6 The prevalence of many micronutrient deficiencies in many countries is highest
in population groups such as adolescents and women of childbearing age (Bartley et al, 2005;
de Benoist et al, 2008; Miller et al, 2016). These groups are most vulnerable to the effects of
iodine and other micronutrient deficiencies should they become pregnant (Zimmermann,
2009a; Vanderpump et al, 2011). As this review has shown selenium, iron and zinc status to
be associated with status of iodine, women of childbearing age and those planning a
pregnancy should be recommended to consume a healthy, balanced diet to ensure they meet
dietary recommendations for these nutrients. Future research and monitoring programmes
should focus on the nutritional status of these population groups and give consideration to
effective strategies to combat multiple micronutrient deficiencies. The long-term impact of
such micronutrient deficiencies during pregnancy on iodine status and thyroid function of
both the mother and offspring should also be monitored.
Conclusions
There is convincing evidence that status of selenium, zinc and iron are positively associated
with iodine status. Deficiencies of selenium, zinc and iron may hinder the effectiveness of
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public health initiatives to improve iodine status and should be corrected to maximise the
benefit of such initiatives.
Micronutrient supplementation appears to have no functional benefits on thyroid hormones.
However, conclusions on the effect of micronutrient supplementation on iodine and thyroid
hormone status were hindered by the lack of studies and the heterogeneity in study
populations and designs. Further randomised controlled trials of adequate power in well-
defined population groups are warranted to investigate the effect of micronutrient
supplementation on iodine status and thyroid function.
Considering the interactions between iodine and other micronutrients an integrated approach
to eradicate iodine deficiency while addressing co-existing micronutrient deficiencies may be
more advantageous than addressing iodine deficiency alone.
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Acknowledgements
The authors thank Sarah Smyth and Joan Atkinson (Subject Librarians, Ulster University) for
their assistance in developing the search strategies. Thanks are extended to those authors who
provided additional information on their articles.
Funding & sponsorship
SMO’K is in receipt of a postgraduate studentship from the Department of Agriculture,
Environment and Rural Affairs (DAERA), Northern Ireland, UK. DAERA had no role in the
design, analysis or writing of this article.
Declaration of interest
The authors have no relevant interests to declare.
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Table 1: Observational evidence of associations between urinary iodine concentration (UIC) and micronutrient status
Study Participants Micronutrient
Micronutrient status measure
Association*N Age (y) Males
(%)Study year Study
locationIodized salt policy
Ҫelik et al. (2014)36 214 6-12 49 ~ Turkey Mandatory: household salt (1995) (1)
Selenium Urine + (r=0.286)
Wang et al. (2012)57 120 20-50 100 ~ China Mandatory: USI (1995) (2)
Selenium Urine + (r=0.773)
Kvicala & Zamrazil (2003)58
287 6-65 ~ ~ Czech Republic
Mandatory: household salt (1947) (3)
Selenium Urine + (r=0.2802)
Ngo et al. (1997)59 599 ~ 0 ~ DR of Congo
No policy in place (59)
Selenium Serum + (r=0.40)
Rasmussen et al. (2011)60
805 18-65 ~ 1997 Denmark No policy in place at study commencement (4)
Selenium Serum + (r=0.2)
Szybinski et al. (2010)61
169 ~ 0 ~ Poland Mandatory: household salt (1996) (3)
Selenium Urine + (r=0.564)
Derumeaux et al. (2003)62
1900 35-60 42 1995 France Voluntary: household salt (4)
Selenium Serum + (M: r=0.13; F: r=0.08)
Kvicala et al. (1997)63
380 6-65 ~ ~ Czech Republic
Mandatory: household salt (1947) (3)
Selenium Serum + (r=0.2330)
Krittaphol et al. (2006)64
515 6-13 50 2002 Thailand Mandatory: Edible salt (5)
Selenium Serum - (r= -0.131)
Erdogan et al. (2001)65
251 9-11 49 1997 Turkey Mandatory: household salt (1)
Selenium Serum NS
Wang et al. (2012)57 120 20-50 100 ~ China Mandatory: USI (1995) (2)
Iron Urine + (r=0.746)
Khatiwada et al. (2015)66
316 6-13 ~ 2013 Nepal Mandatory: USI (6)
Iron Hb; serum iron; TSAT
+ Hb (r= 0.313); serum iron (r=0.136); TSAT (r=0.126)
721
35
Habimana et al. (2013)67
368 25-35 0 2009 DR Congo
Mandatory: USI (7)
Iron SF + (r=0.14)
Khatiwada et al. (2015)66
316 6-13 ~ 2013 Nepal Mandatory: USI (6)
Iron TIBC NS
Thurlow et al. (2006)35
567 6-13 50 2002 Thailand Mandatory: Edible salt (5)
Iron Hb; SF; TfR NS
Ҫelik et al. (2014)36 214 6-12 49 ~ Turkey Mandatory: household salt (1995) (1)
Zinc Urine + (r=0.305)
Wang et al. (2012)57 120 20-50 100 ~ China Mandatory: USI (1995) (2)
Zinc Urine + (r=0.241)
Szybinski et al. (2010)61
169 ~ 0 ~ Poland Mandatory: household salt (1996) (3)
Zinc Urine + (r=0.317)
Thurlow et al. (2006)35
567 6-13 50 2002 Thailand Mandatory: Edible salt (5)
Zinc Serum NS
Hampel et al. (1997)68
5932 M: mean 39F: mean 41
38 1994 Germany Voluntary: USI (4)
Zinc Serum NS
Thurlow et al. (2006)35
567 6-13 50 2002 Thailand Mandatory: Edible salt (5)
Vitamin A Serum retinol NS
Ҫelik et al. (2014)36 214 6-12 49 ~ Turkey Mandatory: household salt (1995) (1)
Copper Urine NS
Ҫelik et al. (2014)36 214 6-12 49 ~ Turkey Mandatory: household salt (1995) (1)
Molybdenum Urine + (r=0.206)
NS= Non significant, n= number of participants, y= Years, % = percentage, USI= Universal salt iodization, Hb= Haemoglobin, TSAT= Transferrin saturation, SF= Serum ferritin, DR= Democratic Republic; TIBC = Total iron binding capacity; TfR= Transferrin receptor; M= males; F= females~ = not reported*Indicates a significant positive (+) or negative (-) association (P<0.05), as assessed by regression analysis, Spearman’s or Pearson’s correlations
722723724725
36
Table 2: Observational evidence of associations between thyroid hormones and micronutrient status
Study Participants Micronutrient
Micronutrient status measure
Associations with thyroid hormones*
N Age (y)
Males (%)
Year study commenced
Study location
Iodized salt policy
TSH TT3 FT3 TT4 FT4 T3:T4 ratio
Tg
Alissa et al. (2009)69
140 16-87 100 ~ Saudi Arabia
Mandatory: USI (1997) (8)
Selenium Erythrocyte GPx
- +
Bratter et al. (1996)70
65 Adults 0 ~ Venezuela
Mandatory: USI (1967) (9)
Selenium Serum NS - NS
Erdogan et al. (2001)65
251 9-11 49 1997 Turkey Mandatory: household salt (1)
Selenium Serum NS NS NS NS
Gashu et al. (2016)71
628 4.5-5 ~ 2011 Ethiopia Mandatory: USI (2011) (71)
Selenium Serum + -
Hagmar et al. (1998)72
68 24-79 100 ~ Latvia Voluntary: USI (10)
Selenium Plasma; SEPP1
- NS NS
Jain RB (2014)39
1409
>20 53 2011 America Voluntary: USI (4)
Selenium Serum NS NS NS NS NS NS
Koukkou et al. (2014)73
47 Mean: 30
0 ~ Greece No policy in place (4)
Selenium Urine NS NS NS
Kvicala et al. (1997)63
380 6-65 ~ ~ Czech Republic
Mandatory: household salt (1947) (3)
Selenium Serum + (F: 6-13y)
-
726
37
Liu et al. (2013)74
1205
43 44 ~ China Mandatory: USI (1995) (2)
Selenium Serum NS
Ngo et al. (1997)59
599 ~ 0 ~ DR of Congo
No policy in place (59)
Selenium Serum NS NS NS
Olivieri et al. (1995)32
109 >20 52 ~ Italy No policy in place until 2005 (4)
Selenium Serum - +
Olivieri et al. (1996)75
109 >20 52 ~ Italy No policy in place until 2005 (4)
Selenium Serum; GPx
+
Ravaglia et al. (2000)38
132 20-107
43 1996 Italy No policy in place (4)
Selenium Serum NS NS NS NS
Rayman et al. (2008)33
501 60-74 41 2000 UK No policy in place (11)
Selenium Plasma NS NS NS NS - +
Vanderpas et al. (1990)76
120 9-42 58 ~ DR Congo
No policy in place (7)
Selenium Serum NS NS NS NS NS
Zagrodzki & Ryszard (2008)77
36 Mean: 24
0 ~ Poland Mandatory: household salt (1996) (3)
Selenium Plasma NS NS
Azizi et al. (2002)78
2917
8-10 ~ 1996 Iran Mandatory: USI (12)
Iron SF NS NS NS
Eftekhari et 94 14-18 0 ~ Iran Mandato Iron SF NS NS NS +
38
al. (2003)79 ry: USI (1992) (12)
Eftekhari et al. (2006)80
103 14-18 0 ~ Iran Mandatory: USI (1992) (12)
Iron SF - +
Khatiwada et al. (2016)81
227 6-12 56 2014 Nepal Mandatory: USI (6)
Iron TSAT; SF - NS NS
Volzke et al. (2006)82
4111
20-79 50 ~ Germany Voluntary: USI (1991) (4)
Iron SF NS NS NS
Yavuz et al. (2004)48
330 12-14 53 ~ Turkey Mandatory: household salt (1995) (1)
Iron Hb NS NS NS
Zimmermann et al. (2007)83
365 16-42 0 1999 Switzerland
Voluntary: USI (4)
Iron Body iron stores; SF
- +
Zimmermann et al. (2007)83
365 16-42 0 1999 Switzerland
Voluntary: USI (4)
Iron TfR + -
Elnour et al. (2000)37
191 1-6 50 1994 Sudan Mandatory: USI (13)
Vitamin A RBP NS +
Ravaglia et al. (2000)38
132 20-107
43 1996 Italy No policy in place (4)
Vitamin A Plasma retinol
20-89y: NS90+ y: -
NS 20=89y: NS90+ y: -
NS
Jain RB (2014)39
1409
>20 53 2011 America Voluntary: USI (4)
Zinc Serum NS NS M: +F: NS
M: -F: NS
M: -F: NS
NS
Moaddab et al. (2009)84
219 Children
~ 2003 Iran Mandatory: USI
Zinc Serum NS NS
39
(12)Olivieri et al. (1996)75
109 >20 52 ~ Italy No policy in place until 2005 (4)
Zinc Serum NS NS NS NS
Ravaglia et al. (2000)38
132 20-107
43 1996 Italy No policy in place (4)
Zinc Plasma NS 20-89y: NS90+ y: +
NS 20-89y: NS>90y: +
Jain RB (2014)39
1409
>20 53 2011 America Voluntary: USI (4)
Copper Serum NS M: NSF: +
NS M: -F: +
M: -F: NS
NS
Ravaglia et al. (2000)38
132 20-107
43 1996 Italy No policy in place until 2005 (4)
Vitamin E Plasma α-tocopherol
NS NS NS NS
Chailurkit et al. (2013)40
2018
15-98 ~ 2008 Thailand Mandatory: Edible salt (5)
Vitamin D Serum 25(OH)D
15-44y: -45y+: NS
Zhao et al. (2014)41
50 22-36 0 2005 China Mandatory: USI (2)
Vitamin D Serum 25(OH)D
NS NS NS NS
NS= Non significant, n= number of participants, y= Years, % = percentage, USI= Universal salt iodization M= males; F= females, TSH= Thyroid stimulating hormone, TT3= Total triiodothyronine, FT3= Free triiodothyronine, TT4= Total thyroxine, FT4= Free thyroxine, T3:T4 ratio= triiodothyronine: thyroxine ratio, Tg= Thyroglobulin, DR= Democratic Republic, SF= Serum ferritin, TSAT= Transferrin saturation, Hb= Haemoglobin, TfR= Transferrin receptor, GPx= glutathione peroxidase, SEPP1= Selenoprotein P, RBP= Retinol binding protein. 25(OH)D= 25-hydroxyvitamin D. ~ = not reported*Indicates a significant positive (+) or negative (-) association (P<0.05), as assessed by regression analysis, Spearman’s or Pearson’s correlations
727728729730731732
733
40
Table 4: Effect of micronutrient supplementation on iodine and thyroid hormones
Study Participants Intervention description (micronutrient dose per day)
Duration Effect of intervention on iodine and thyroid hormones
N Age (y) Males (%)
UIC TSH TT3 FT3 TT4 FT4
Contempre et al. (1992)108
53 Mean: 14 77 Selenium (50µg) 2 months NS NS ↓ ↓
Hawkes et al. (2003)109 12 I: mean: 31C: mean: 35
100 High Se diet (297µg) 99 days ↑ ↓ NS
Hawkes et al. (2008)110 54 18-45 100 Selenium (300µg) 48 weeks NS NS NSMao et al. (2014)111 230 Pregnant
women0 Selenium (60µg) 12-14 weeks
gestation - deliveryNS NS
Olivieri et al. (1995)32 36 Mean: 85 22 Selenium (100µg) 3 months NS NS ↓ NSRayman et al. (2008)33 501 60-74 41 i) Selenium (100µg)
ii) Selenium (200µg)iii) Selenium (300µg)
26 weeks NS NS NS NS NS
Thomson et al. (2011)112
143 60-80 ~ Selenium (100µg) 8 weeks NS NS NS
Thomson et al. (2001)113
52 Mean: 28 0 Selenium (50µg) Early pregnancy to one year post partum
NS
Thomson et al. (2009)114
100 60-80 45 Selenium (100µg) 12 weeks NS NS NS
Winther et al. (2015)115
491 60-74 88 i) Selenium (100µg)ii) Selenium (200µg)iii) Selenium (300µg)
5 years NS NS NS
Andersson et al. (2008)116
458 5-15 53 Iron (2mg/Fe/g salt) 10 months NS
Eftekhari et al. (2006)117
103 14-18 0 Iron (214mg) 12 weeks NS NS ↑ NS ↑ NS
Eftekhari et al. (2007)118
103 14-18 0 Iron (214mg) 12 weeks NS ↑ NS ↑ ↑
Hass et al. (2014)119 245 18-55 0 Iron(3.3mg/Fe/g salt) 8 months NSHess et al. (2002)120 169 5-14 69 Iron (34mg) 16 weeks NSZimmermann et al. (2002)121
377 6-15 51 Iron (7-12mg) 9 months NS NS ↑
Zimmermann et al. (2004)122
163 6-15 51 Iodised salt + iron (2mg/Fe/g salt)
10 months NS
734735
41
Farhangi et al. (2012)46
84 17-50 0 Vitamin A (25,000IU) 16 weeks ↓ ↑ ↓
Zimmermann et al. (2007)45
404 5-14 86 Vitamin A (200,000IU) 6 months NS ↓ NS
Kandhro et al. (2009)34 358 16-30 46 Zinc (30µg) 6 months ↓ ↑ ↑
NS= Non significant, n= number of participants, y= Years, % = percentage, I= Intervention, C= Control, UIC= Urinary iodine concentration, TSH= Thyroid stimulating hormone, TT3= Total triiodothyronine, FT3= Free triiodothyronine, TT4= Total thyroxine, FT4= Free thyroxine~ = not stated↓= significantly decreased following supplementation (P<0.05), ↑= significantly increased following supplementation (P<0.05)
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