pure.ulster.ac.uk · web viewarticle type: systematic review. title: micronutrient status, iodine...

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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: [email protected]

Tel: +44 (0) 28 7012 3147

Fax Number: +44 (0) 28 7012 4965

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mailto:[email protected]

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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)


Kvicala & Zamrazil (2003)58

287 6-65 ~ ~ Czech Republic

Mandatory: household salt (1947) (3)


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)


Szybinski et al. (2010)61

169 ~ 0 ~ Poland Mandatory: household salt (1996) (3)


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




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


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)


316 6-13 ~ 2013 Nepal Mandatory: USI (6)

Iron TIBC NS

Thurlow et al. (2006)35


Iron Hb; SF; TfR NS


Zinc Urine + (r=0.305)



Szybinski et al. (2010)61

169 ~ 0 ~ Poland Mandatory: household salt (1996) (3)




Zinc Serum NS

Hampel et al. (1997)68

5932 M: mean 39F: mean 41

38 1994 Germany Voluntary: USI (4)

Zinc Serum NS



Vitamin A Serum retinol NS


Copper Urine NS


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



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


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


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


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 - +


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

- +


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 +


132 20-107


Vitamin A Plasma retinol

20-89y: NS90+ y: -

NS 20=89y: NS90+ y: -

NS

Jain RB (2014)39

1409


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


Zinc Serum NS NS NS NS


132 20-107


Zinc Plasma NS 20-89y: NS90+ y: +

NS 20-89y: NS>90y: +

Jain RB (2014)39

1409


Copper Serum NS M: NSF: +

NS M: -F: +

M: -F: NS

NS


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


52 Mean: 28 0 Selenium (50µg) Early pregnancy to one year post partum

NS


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


103 14-18 0 Iron (214mg) 12 weeks NS NS ↑ NS ↑ NS


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 ↑


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 ↓ ↑ ↓


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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pure.ulster.ac.uk · web viewarticle type: systematic review. title: micronutrient status, iodine...

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