Abstract
Background: Thyroglobulin, produced exclusively by the thyroid gland, has been proposed to be a more sensitive biomarker of iodine status than thyrotropin or the thyroid hormones triiodothyronine and thyroxine. However, evidence on the usefulness of thyroglobulin (Tg) to assess iodine status has not been extensively reviewed, particularly in pregnant women and adults.
Summary: An electronic literature search was conducted using the Cochrane CENTRAL, Web of Science, PubMed, and Medline to locate relevant studies on Tg as a biomarker of iodine status. Since urinary iodine concentration (UIC) is the recommended method to assess iodine status in populations, only studies that clearly reported both Tg and UIC were included. For the purpose of this review, a median Tg <13 μg/L and a median UIC ≥100 μg/L (UIC ≥150 μg/L for pregnant women) were used to indicate adequate iodine status. We excluded studies conducted in subjects with either known thyroid disease or those with thyroglobulin antibodies. The search strategy and selection criteria yielded 34 articles of which nine were intervention studies. The majority of studies (six of eight) reported that iodine-deficient pregnant women had a median Tg ≥13 μg/L. However, large observational studies of pregnant women, including women with adequate and inadequate iodine status, as well as well-designed intervention trials that include both Tg and UIC, are needed. In adults, the results were equivocal because iodine-deficient adults were reported to have median Tg values of either <13 or ≥13 μg/L. Only studies in school-aged children showed that iodine-sufficient children typically had a median Tg <13 μg/L. Some of the inconsistent results may be partially explained by the use of different methodological assays and failure to assess assay accuracy using a certified reference material.
Conclusions: These data suggest that Tg does hold promise as a biomarker of iodine deficiency. However, it is associated with limitations. A median Tg cutoff of 13 μg/L warrants further investigation, particularly in adults or pregnant women, as there is a lack of both observational and intervention studies in these groups.
Introduction
Iodine is needed by the thyroid gland to produce thyroid hormones required for normal growth and development (1). Insufficient iodine intake causes iodine deficiency, which affects millions of people worldwide (2). Iodine deficiency is most commonly assessed by measuring urinary iodine concentration (UIC) because approximately 90% of dietary iodine is excreted in the urine (3). Due to large intra- and interindividual variation, UIC cannot be used to assess iodine status in individuals and is only appropriate for groups (4). A median UIC <100 μg/L in children and nonpregnant adults indicates iodine deficiency (5). Since UIC only assesses recent iodine intake (i.e., days) (5), a low UIC in a single urine sample does not necessarily indicate iodine deficiency in that individual (4). In addition to UIC, other measures of iodine status include thyroid volume, thyrotropin (TSH), triiodothyronine (T3), and thyroxine (T4); each of these indices has limitations. Thyroid volume reduces gradually (i.e., months to years) in previously iodine-deficient subjects (6). TSH, T3, and T4 concentrations typically fall within the normal range in mildly iodine-deficient populations of school-aged children and adults (7,8) such as those who live in developed countries such as the United States, the United Kingdom, Australia, and New Zealand. Another biomarker of iodine status sensitive to an intermediate change (i.e., weeks to months) in iodine intake would be useful.
Thyroglobulin (Tg) plays an important role in the synthesis of thyroid hormones T3 and T4 (9). It is a glycoprotein comprising two 330 kDa protein chains synthesized in the thyrocyte (10). After synthesis, Tg is transported and stored in the follicular colloid of the thyrocyte (11). In the follicular lumen, the tyrosine residues of Tg undergo iodination to produce mono- (MIT) and di-iodotyrosines (DIT) catalyzed by thyroid peroxidase (12) and hydrogen peroxide (13). Subsequent coupling of these iodotyrosines produces T3 and T4 (14,15). Tg is pinocytosed into the thyroid cell (16) and undergoes proteolysis by lysosomes to release T3 and T4 (17), which are then secreted into the bloodstream (18).
When iodine intake is insufficient, low circulating levels of T4 stimulate the release of thyrotropin-releasing hormone from the pituitary gland, which subsequently increases the production of TSH. In addition to increasing the synthesis and proteolysis of Tg, TSH also stimulates the growth and division of the follicular cells, which causes the thyroid gland to enlarge (i.e., goiter) (19). In iodine deficiency, an increased amount of Tg is released into the blood (20), which is positively correlated with thyroid volume (21). For example, healthy adults have a mean Tg concentration ranging from 5 to 14 μg/L (22–27). In contrast, adults with endemic goiter have a mean Tg ranging from 94 to 208 μg/L (28–30). Recently, experts attending a National Institutes of Health workshop (31) recommended that Tg be used in the evaluation of iodine status.
The most common use of Tg is to monitor the treatment of patients with differentiated thyroid cancer (DTC) (32). Several review articles have focused on Tg monitoring in patients with DTC (11,33,34) or the performance of different assays used for monitoring DTC (35,36). The evidence on the usefulness of Tg in patients with DTC is well established. However, data on the effectiveness of Tg to assess iodine status in healthy populations is scarce. This review will report on: first, the analytical issues of Tg methods; second, observational studies measuring Tg to assess iodine status in healthy populations of pregnant women, newborns, children, and adults; and third, intervention studies investigating the effect of iodine supplementation on Tg in populations of pregnant women, newborns, children, and adults. This information will be used to determine if Tg can be used as a biomarker to assess iodine status.
Search Strategy
We conducted an electronic literature search using the Cochrane CENTRAL, Web of Science, PubMed, and Medline (OvidSP) to locate relevant studies published in English between January 1960 and October 2013 using Tg as a biomarker of iodine status. We used the following combined keywords: serum thyroglobulin, thyroglobulin, blood, children, infants, adults, pregnant women, pregnancy, maternal iodine status, iodine status, iodine deficiency, iodine insufficiency, iodine sufficiency, and iodine supplementation. We also located additional studies from references in the retrieved articles. Since UIC is the recommended biomarker of iodine status in populations (5), only studies that clearly report both Tg and UIC were included. We excluded studies conducted in subjects with either known thyroid disease or those with thyroglobulin antibodies (TgAb) because such subjects can have falsely low or high Tg that are not caused by insufficient iodine intake. The search resulted in 34 articles (i.e., 38 studies) being selected (Table 1). Of these, nine were randomized controlled trials, two were nonrandomized controlled trials, three were cohort observational studies, 23 were cross-sectional studies (10 multicenter), and one was a monitoring report of iodization programs that included a measurement before the introduction of iodized salt to a measurement after the introduction of iodized salt. In order to investigate the consistency of the relationship between iodine status as determined by UIC and Tg more clearly, for those studies that reported this information for more than one group, we considered each of these groups separately (i.e., one study of pregnant women and their newborns (37); one study of pregnant women and adults (38); one study of children and adults (30); three studies of children living in different regions (39) or countries (40,41); and seven studies of adults living in different regions (21,25,42–44) or countries (45,46)).
Table 1.
Types of Tg and TgAb Assays in Studies Assessing UIC and Tg in Various Population Groups
| Studies | Year | Tg assay | TgAb assay |
|---|---|---|---|
| Pregnant women | |||
| Observational | |||
| Pedersen et al. (38)a | 1988 | RIA | RIA |
| Laurberg et al. (76) | 1994 | Yes (NR) | NA |
| Eltom et al. (78) | 2000 | RIA | NA |
| Costeira et al. (79) | 2010 | RIA | RIA |
| Brucker-Davis et al. (74) | 2012 | IRMA | NA |
| Raverot et al. (75) | 2012 | IRMA | NA |
| Andersen et al. (37)b | 2013 | ILMA | RIPA |
| Brough et al. (77) | 2013 | ICMA | AA |
| Intervention | |||
| Liesenkötter et al. (80) | 1996 | RIA | NA |
| Nøhr et al. (81) | 2000 | ILMA | RIPA |
| Santiago et al. (82) | 2013 | ICMA | NA |
| Newborns | |||
| Observational | |||
| Andersen et al. (37)b | 2013 | ILMA | RIPA |
| Intervention in pregnancy | |||
| Pedersen et al. (85) | 1993 | ICMA | Tg recovery |
| Glinoer et al. (86) | 1995 | RIA | RIA |
| Children | |||
| Observational | |||
| Simsek et al. (39) | 2003 | ICMA | NA |
| Zimmermann et al. (40)c | 2006 | FIA | RIA |
| Bayram et al. (30)d | 2009 | RIA | RIA |
| Skeaff et al. (73) | 2012 | RIA | NA |
| Skeaff and Lonsdale-Cooper (55) | 2013 | ECLIA | NA |
| Zimmermann et al. (41) | 2013 | FIA | RIA |
| Intervention | |||
| Benmiloud et al. (89) | 1994 | ILMA | NA |
| Zimmermann et al. (47) | 2003 | FIA | RIA |
| Zimmermann et al. (40)c | 2006 | FIA | NA |
| Gordon et al. (64) | 2009 | RIA | RIA |
| Adults | |||
| Observational | |||
| Fenzi et al. (25) | 1985 | IRMA | HA |
| Gutekunst et al. (45) | 1986 | ILMA | NA |
| Pedersen et al. (38)a | 1988 | RIA | RIA |
| Hintze et al. (90) | 1991 | ELISA | RIA |
| Laurberg et al. (46) | 1998 | ILMA | RIPA |
| Knudsen et al. (44) | 2001 | ILMA | RIA |
| Thomson et al. (91) | 2001 | RIA | NA |
| Rasmussen et al. (43) | 2002 | ILMA | RIA |
| Teng et al. (42) | 2006 | ICMA | ICMA |
| Bayram et al. (30)d | 2009 | RIA | RIA |
| Vejbjerg et al. (21) | 2009 | ILMA & FIA | RIA & FIA |
| Cahoon et al. (72) | 2013 | ICMA | RIA & ICMA |
| Intervention | |||
| Thomson et al. (63) | 2009 | ICMA | ICMA |
| Soriguer et al. (92) | 2011 | IRMA | RIA |
Included pregnant women and adults.
Included pregnant women and newborns.
Counted as one article.
Included children and adults.
AA, agglutination assay; ECLIA, electrochemiluminescence immunoassay; ELISA, enzyme-linked immunosorbent assay; FIA, fluoroimmunoassay; HA, hemagglutination assay; ICMA, immunochemiluminescence assay; ILMA, immunoluminometric assay; IRMA, immunoradiometric assay; NA, not assessed; NR, not reported; RIA, radioimmunoassay; RIPA, radioimmunoprecipitation assay; Tg, thyroglobulin; TgAb, thyroglobulin antibodies; UIC, urinary iodine concentration.
Discussion
Methods to measure Tg concentration
Tg can be measured using either immunometric assay (IMA) or radioimmunoassay (RIA) (35). Of the 34 articles measuring Tg (Table 1), the predominant Tg assay used was RIA (27%), followed by various IMAs, including immunoluminometric assay (22%), immunochemiluminescence assay (21%), immunoradiometric assay (12%), fluoroimmunoassay (10%), enzyme-linked immunosorbent assay (3%), electrochemiluminescence immunoassay (3%), and not reported (3%). Only one article (21) measured Tg using two different types of assays. A dried blood spot method using fluoroimmunoassay (FIA) (40) has been developed by Zimmermann et al. to assess Tg in children (5). Though Tg obtained from a dried blood spot was well correlated with serum samples (r=0.98, p<0.0001) in healthy children (n=29) (47), this relationship has yet to be validated in populations of adults including pregnant women. Furthermore, the dried blood spot method has not been reproduced in other laboratories.
Studies of Tg using RIA were first published in the 1960s. Several of these early studies (48–50) reported that Tg was undetectable in some healthy participants. For example, a small study conducted by Hjort et al. (48) used a RIA with a limit of detection (LoD) of 50 μg/L and found that Tg was undetected in all 12 healthy subjects, indicating that these subjects would likely have had Tg concentrations ≤50 μg/L. In contrast, Torrigiani et al. (49) detected Tg in 60–70% of healthy subjects (n=111) when they used a RIA with a LoD of 10 μg/L; van Harle et al. (50) detected Tg in 74% of healthy subjects (n=95) using a RIA with a LoD of 1.6 μg/L. Therefore, early RIAs had a relatively poorer functional sensitivity compared with first-generation Tg assays (0.5–1.0 μg/L) developed in the 1980s (51,52) and second-generation Tg assays (≤0.1 μg/L) in use since the early 2000s (53,54); studies using first-generation Tg assays (21,55) did not report undetectable Tg in any healthy subjects.
Tg has been reported to be method dependent (56–58), and the interassay variation can vary between 43% and 65% in healthy subjects (35,57,59). To overcome interassay variation and allow for comparisons between studies, a certified Tg reference material (i.e., CRM-457) has been produced as a quality-control material for assay standardisation (60). Some but not all types of Tg assays have been standardized against CRM-457 in-house by the manufacturers (61). However, Tg CRM-457 only reduces interassay variation by 14–27% (59). It is suggested that this is because current Tg assays are unable to identify the heterogeneity of Tg epitopes (52,62). Of 34 articles measuring Tg (Table 1), only four (40,41,63,64) used Tg CRM-457 as an external quality control.
Another issue with regard to the measurement of Tg is the presence of TgAb. When a RIA is used, a subject positive for TgAb will most likely have a higher Tg value, while IMA tends to lower Tg in TgAb-positive subjects (33,65). Thus, subjects who have a positive test for TgAb should be excluded from the results if Tg is used as a biomarker of iodine status in a population. In adults, studies (66–69) have found that 3–13% of adults have TgAb. However, in children, the prevalence of TgAb is lower (70,71), and Zimmermann et al. (47) suggest that screening for TgAb in this age group is not necessary. Twenty-two of 34 studies measured TgAb prior to Tg measurement (Table 1). Of these, the predominant TgAb assay used was a RIA (58%), followed by the radioimmunoprecipitation assay (14%), immunochemiluminescence assay (12%), Tg recovery (5%), hemagglutination assay (5%), agglutination assay (5%), and FIA (2%). Only two articles (21,72) measured TgAb using two different types of TgAb assays.
In a large multicenter study of healthy children aged 5–14 years, Zimmermann et al. reported a reference range for Tg of 4–40 μg/L as determined by FIA (40). This is similar to reference ranges reported for adults of 3–40 μg/L using both RIA and IMA methods (65,68). We did not identify any consistent effects of age or sex on Tg. Only one study (73) reported that Tg decreased with advancing age. In 1994, the WHO/ICCIDD/UNICEF suggested that a median Tg concentration <10 μg/L indicates adequate iodine status in populations of school-age children. However, in 2007, the WHO/ICCIDD/UNICEF, although acknowledging that Tg could be used an indicator of iodine status, did not provide a cutoff for Tg. More recently, Zimmermann et al. (41) conducted a large multicenter study of children (n=2512) from 12 countries with varying iodine status, and suggest that a median Tg concentration <13 μg/L and/or <3% of Tg values >40 μg/L be used as a biomarker of adequate iodine status in children and, with caution, in adults. To date, the cutoff of 13 μg/L and/or <3% of Tg values >40 μg/L has not been examined in younger children or pregnant women. Because no studies have reported the percentage of Tg values >40 μg/L in populations, for the purpose of this review, a median Tg <13 μg/L and a median UIC ≥100 μg/L (UIC ≥150 μg/L for pregnant women) were used to indicate adequate iodine status.
Pregnant women
Eight observational studies measuring Tg in iodine-deficient pregnant women aged between 15 and 46 years were identified (Table 2). Six of eight studies (37,38,74–77) reported that iodine-deficient pregnant women (either first, second, or third trimester, or at delivery) had a median Tg ≥13 μg/L (range 16–67 μg/L). Two of the eight studies (78,79) assessed Tg concentration in iodine-deficient women throughout their pregnancy (i.e., in each trimester); in one study (79), a median Tg <13 μg/L was observed in all three trimesters, and in one study (78), a Tg ≥13 μg/L was reported in the first and third trimesters, but it was <13 μg/L in the second trimester. Although six of eight studies (37,38,74,75,77,79) collected information on the use of iodine supplements in pregnancy, of these, only one study (37) reported that the Tg concentration of women taking iodine supplements was significantly lower compared with women who did not take supplements (i.e., difference of ∼15 μg/L). We are unaware of any published studies of pregnant women with adequate iodine status that include measures of both UIC and Tg.
Table 2.
Observational Studies Measuring Tg in Relation to Iodine Status in Pregnant Women
| Authors | Age (years)a; nb; country | Trimesters | UICc (μg/L) | Tgc (μg/L) | Findings | Comments | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Pedersen et al. (38) | 21–38; n=20; Denmark | 3rd | 52d | 67 | Suggested high Tg might be due to an increase in iodine intake in pregnancy | Women did not take iodine supplements. | ||||||
| Laurberg et al. (76) | NR; n=20; Denmark, Sweden, and Iceland | At term | Denmark | 39 | Denmark | 29.7 | Women living in Denmark had a significantly higher median Tg than those living in Sweden and Iceland (p<0.05) | No data on supplement use | ||||
| Sweden | 78 | Sweden | 15.9 | |||||||||
| Iceland | 118 | Iceland | 15.9 | |||||||||
| Eltom et al. (78) | 20–40; n=48; Sweden and Sudan | 1st, 2nd, and 3rd | Trimesters | Trimesters | Sudanese women had a significantly higher median Tg than the Swedish women in the 1st (p<0.05), 2nd (p<0.001), and 3rd trimesters (p<0.01). | Women were followed throughout pregnancy; no data on supplement use | ||||||
| 1st | 2nd | 3rd | 1st | 2nd | 3rd | |||||||
| Swedish | 89 | 89 | 76 | Swedish | 15.5 | 10.5 | 18.0 | |||||
| Sudanese | 38 | 25 | 38 | Sudanese | 27.5 | 25.0 | 30.0 | |||||
| Costeira et al. (79,93)e | 29.9; n=118; Portugal | 1st, 2nd and 3rd trimester, and 1 year PP | Trimester | Trimester | Tg in 1st and 2nd trimester increased from 11 to 13 μg/L in 3rd trimester | Women were followed throughout pregnancy; they did not take iodine supplements | ||||||
| 1st | 65 | 1st | 11.0 | |||||||||
| 2nd | 57 | 2nd | 11.0 | |||||||||
| 3rd | 70 | 3rd | 12.7 | |||||||||
| 1 year PP | 40 | 1 year PP | 9.7 | |||||||||
| Brucker-Davis et al. (74) | 18–40; n=110; France | 1st | 116 | 17.4 | Tg was not correlated with UIC | Women did not take iodine supplements | ||||||
| Raverot et al. (75) | 15.3–45.7; n=228; France | 1st, 2nd, and 3rd | Trimester | Trimester | Tg in the 1st, 2nd, or 3rd trimesters were not significantly different (p>0.05) | Women did not take iodine supplements | ||||||
| 1st | 69 | 1st | 16.6 | |||||||||
| 2nd | 91 | 2nd | 15.7 | |||||||||
| 3rd | 91 | 3rd | 16.2 | |||||||||
| Andersen et al. (37) | 27.3; n=140; Denmark | At term | No supplements | NR | No supplements | 29.36 | Women taking supplements (i.e., 150 μg I/day) had a significantly lower Tg than those not taking supplements (p<0.001) | |||||
| Supplements | NR | Supplements | 14.06 | |||||||||
| All | 41f | All | 22.96 | |||||||||
| Brough et al. (77) | 31; n=70; New Zealand | 3rd trimester or breastfeeding for >3 weeks | 3rd trimester | 85 | 3rd trimester | 15.9 | Tg was not correlated with UIC in women in the 3rd trimester and at PP | 70% pregnant women and 36% breastfeeding women used iodine supplements ranging from 100 to 150 μg I/day | ||||
| PP | 74 | PP | 13.9 | |||||||||
Range used unless mean reported.
Only subjects with no known thyroid disease or negative for TgAb were included.
Median used unless mean or geometric mean reported.
UIC reported as μg/g creatinine.
Tg was reported in Costeira et al. (79); UIC and the data on supplement use were reported in Costeira et al. (93). These two studies were counted as one study (79).
Geometric mean.
I, iodine; PP, postpartum.
Three intervention studies investigating the effect of iodine supplementation on Tg in iodine-deficient pregnant women were identified (Table 3). One of the studies (80) assessed Tg concentration in the first trimester before supplementation and then again at two weeks postpartum; one study (81) assessed Tg in the first and third trimesters; and one study (82) assessed Tg in all three trimesters and again 12–24 weeks postpartum. Tg concentrations in women in the first trimester (i.e., at baseline before supplementation) ranged from 13 to 25 μg/L, and postpartum, in women that had received any type of additional iodine (i.e., supplements or iodized salt), Tg ranged from 8 to 18 μg/L. Of the two studies with postpartum data (80,82), only one study (80) reported that women taking iodine supplementation in pregnancy had a postpartum median Tg <13 μg/L. However, the interpretation of these findings is confounded by differences in study designs, including a lack of a placebo group, relatively small sample sizes (n=66–131), varying levels and types of supplemental iodine (iodized salt or supplements containing 150–300 μg iodine per day), duration of follow-up (2–24 weeks postpartum), and use of different Tg assays.
Table 3.
Intervention Studies Investigating the Effect of Iodine Supplementation on Tg in Pregnant Women
| Authors | Age (years)a; country | Study designb | Groupc | UIC (μg/L)d | Tg (μg/L)d | Findings | Comments | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Liesenkötter et al. (80) | 21–40; Germany | Women (n=108) randomized to receive either iodine supplements (300 μg I/day) or no iodine until 0.5 months PP | 1st trimestere | 0.5 months PPe | 1st trimesterg | 0.5 months PPg | Women taking iodine supplements did not have a significantly lower Tg in the 1st trimester and 0.5 months PP | Unequal group sizes (38 women in iodine supplemented group while 70 women in no iodine group); 14 women had goiter previously | |||||
| 0 μg | 55 | 50f | 16.6 | 13.5 | |||||||||
| 300 μg | 49 | 105 | 16.5 | 8.3 | |||||||||
| Nøhr et al. (81) | 18–35; Denmark | Women (n=66) randomized to receive a vitamin and mineral tablet with 0 (placebo) or 150 μg I daily until 9 months PP | Trimesters | Trimesters | Women taking supplements had a significantly lower Tg than women taking placebo in the 3rd trimester (p=0.001) | All women were thyroid peroxidase antibody-positive; PP data for Tg was available from a figure only | |||||||
| 0 μg | 1st | 3rd | 1st | 3rd | |||||||||
| 150 μg | 51 | 53 | 17.1 | 19.4 | |||||||||
| 51g,h | 105 | 18.0f,g | 14.1 | ||||||||||
| Santiago et al. (82) | 31; Spain | Women (n=131) randomized to receive either IS, 200 μg, or 300 μg I daily until 3–6 months PP | Trimestersg | 3–6 months PP | Trimestersg | 3–6g months PP | There was no significant difference in Tg within groups (p=0.13) or between groups (p=0.21) | All pregnant women were not iodine supplemented before enrolling in the study; 32% of pregnant women took IS at least 1 year before their pregnancy | |||||
| 1st | 2nd | 3rd | 1st | 2nd | 3rd | ||||||||
| IS | 145 | 130 | 144 | NA | 21.3 | 22.7 | 22.1 | 16.7 | |||||
| 200 μg | 117 | 177 | 166 | NA | 25.4 | 21.6 | 24.8 | 14.9 | |||||
| 300 μg | 137 | 222 | 212 | NA | 13.0 | 8.4 | 13.9 | 18.1 | |||||
Range used unless mean reported.
Only subjects with no known thyroid disease or negative for thyroglobulin antibody were included.
Actual quantity of iodine from supplement; Liesenkötter et al. (80) and Santiago et al. (82) used iodine supplements in the form of KI.
Median used unless mean reported.
UIC reported as μg/g creatinine.
Estimated value from a figure.
Mean.
Estimated value from a table.
IS, iodized salt; KI, potassium iodide.
In summary, it appears that the majority studies typically report that iodine-deficient pregnant women have a median Tg ≥13 μg/L. Furthermore, iodine supplementation does not consistently decrease Tg below this cutoff either during pregnancy or postpartum, although this may reflect inadequate supplementation, as UIC did not reach recommended cutoffs. More large observational studies of pregnant women, including women with adequate and inadequate iodine status, as well as good intervention trials that include both Tg and UIC, are required before conclusions can be drawn about the usefulness of Tg as a biomarker of iodine status in pregnancy. Another consideration is whether Tg in pregnancy needs to be trimester specific, as is suggested for thyroid hormones such as TSH (83) and T4 (84).
Newborns
Three studies that measured Tg in cord blood from newborns were identified (Tables 4 and 5). Two of the three studies (85,86) were supplementation trials of mothers during pregnancy. The Tg concentration of newborns born to mothers receiving a placebo or who did not take supplements in pregnancy ranged from 62 to 113 μg/L, while in the newborns of mothers who took iodine supplements, Tg ranged from 31–65 μg/L. The usefulness of measuring Tg in newborn cord blood is questionable. A more commonly used and relatively accessible biomarker to assess iodine status in newborns is neonatal TSH collected by heel prick two to three days after birth (5).
Table 4.
Observational Studies Measuring Tg in Relation to Iodine Status in Newborns, Children, and Adults
| Authors | Age (years)a; nb; country | UICc (μg/L) | Tgc (μg/L) | Findings | Comments | ||||
|---|---|---|---|---|---|---|---|---|---|
| Newborns | |||||||||
| Andersen et al. (37) | Newborns; n=140; Denmark | No supplements | — | No supplements | 61.6d | Infants of mothers taking iodine supplements of 150 μg I/day had a significantly lower Tg than infants born to mothers not taking supplements (p<0.001) | A lag period (i.e., 5 days) between the collection of urine from infant and cord blood samples | ||
| Supplements | — | Supplements | 31.1d | ||||||
| All | 44d | All | 50.0d | ||||||
| Children | |||||||||
| Simsek et al. (39) | 8–10; n=727; Turkey | Urbane | Urbane | Severely iodine deficient children had a significantly lower Tg than children with mild to moderate iodine deficiency and iodine sufficient children (p<0.001); Tg was negatively correlated with urinary iodine (r=− 0.27, p<0.001). | |||||
| Düzce | 96 | Düzce | 10.9 | ||||||
| Bolu | 108 | Bolu | 8.4 | ||||||
| Rural | Rural | ||||||||
| Yiğilca | 13 | Yiğilca | 59.1 | ||||||
| Mudurnu | 46 | Mudurnu | 27.2 | ||||||
| Akçakoca | 71 | Akçakoca | 14.2 | ||||||
| Gerede | 75 | Gerede | 12.8 | ||||||
| Zimmermann et al. (40) | 5–14; n=710; 5 countries | Countries: | Countries: | Purpose of this study was to determine the Tg reference interval of children (i.e., 4–40 μg/L). Of the five countries, children from three countries had high Tg despite being iodine sufficient | |||||
| Bahrain | 177 | Bahrain | 19.3 | ||||||
| Peru | 161 | Peru | 11.6 | ||||||
| South Africa | 266 | South Africa | 18.4 | ||||||
| China | 234 | China | 13.3 | ||||||
| Switzerland | 130 | Switzerland | 11.2 | ||||||
| All | 198 | All | 14.5 | ||||||
| Bayram et al. (30) | 10–14; n=109; Turkey | 51e | 49.9e | Nongoitrous children had a significantly lower Tg than goitrous children (p<0.001); Tg was negatively correlated with urinary iodine (r=− 0.611, p<0.05) | |||||
| Skeaff et al. (73) | 5–14; n=1153; New Zealand | Age (years) | Age (years) | Iodine sufficient children had a significantly lower Tg than iodine deficient children (p<0.001) | |||||
| 5–7 | 63 | 5–7 | 16.2 | ||||||
| 8–10 | 67 | 8–10 | 12.5 | ||||||
| 11–14 | 75 | 11–14 | 11.1 | ||||||
| All | 68 | All | 12.9 | ||||||
| Skeaff and Lonsdale-Cooper (55) | 8–10; n=147; New Zealand | 113 | 10.8 | UIC indicated adequate iodine status but Tg indicated mild iodine deficiency, suggesting that the children still had thyroid enlargement | Correction factor of 0.588 used to adjust for intraassay variation in Tg values between ECLIA and RIA method | ||||
| Zimmermann et al. (41) | 6–12; n=2512; 12 countries | Countries: | Countriesd: | Tg followed a U-shaped curve from severely deficient to excessive iodine intake as assessed by UIC | |||||
| Morocco | 16 | Morocco | 25.5 | ||||||
| Tajikistan | 52 | Tajikistan | 10.9 | ||||||
| Switzerland | 137 | Switzerland | 10.5 | ||||||
| Philippines | 154 | Philippines | 13.1 | ||||||
| Bahrain | 178 | Bahrain | 18.0 | ||||||
| Peru | 197 | Peru | 11.5 | ||||||
| Croatia | 205 | Croatia | 11.3 | ||||||
| China | 235 | China | 12.6 | ||||||
| Indonesia | 235 | Indonesia | 9.8 | ||||||
| Paraguay | 257 | Paraguay | 13.6 | ||||||
| South Africa | 282 | South Africa | 18.6 | ||||||
| Tanzania | 338 | Tanzania | 17.6 | ||||||
| All | 151 | All | 13.3 | ||||||
| Adults | |||||||||
| Fenzi et al. (25) | 38.8; n=840; Italy | Endemic goiter | 44e,f | Endemic goiter | 49.9e | Adults living in an iodine sufficient area had a significantly lower Tg than adults living in an endemic goiter area (p<0.01); Tg was negatively correlated with urinary iodine (r=− 0.185, p=0.001) | |||
| Iodine sufficient | 88e,f | Iodine sufficient | 9.5e | ||||||
| Gutekunst et al. (45) | ≥17; n=1291; Germany and Sweden | Germany | 63g | Germany | 43.0 | German adults had a significantly lower Tg than Swedish adults (p<0.0001) | |||
| Sweden | 141g | Sweden | 21.2 | ||||||
| Pedersen et al. (38) | 22–37; n=20; Denmark | 42g | 32.5 | Six adults were positive for TgAb but were not included in Tg results | |||||
| Hintze et al. (90) | 60–97; n=286; Germany | 64g | 8.9 | Adults with no goiter had a significantly lower median Tg than adults with goiter (p<0.001) | |||||
| Laurberg et al. (46) | 66–70; n=523; Denmark and Iceland | Denmark | 38 | Denmark | 15.5 | In Denmark (Jutland), 14.2% adults living had Tg >50 μg/L; while in Iceland, 3.4% adults had Tg >50 μg/L | Differences in Tg between adults living Denmark and Iceland not reported | ||
| Iceland | 150 | Iceland | 9.5 | ||||||
| Knudsen et al. (44) | 18–65; n=3759; Denmark | Copenhagen | 68 | Copenhagen | 11.3 | Adults living in Copenhagen had a significantly lower Tg than adults living in Aalborg (p<0.001) | Adults included those who were taking iodine supplements. | ||
| Aalborg | 53 | Aalborg | 15.2 | ||||||
| Thomson et al. (91) | 18–49; n=233; New Zealand | 54 | 5.1 | Tg was negatively correlated with UIC (r=− 0.210, p=0.003) | |||||
| Rasmussen et al. (43) | 18–65; n=4649; Denmark | Copenhagen | 68 | Copenhagen | 11.5 | Adults living in Copenhagen had a significantly lower Tg than adults living in Aalborg (p<0.001); Tg was negatively correlated with iodine intake | Adults included pregnant women (1.3%) and lactating women (1.8%) | ||
| Aalborg | 53 | Aalborg | 15.4 | ||||||
| Teng et al. (42) | 14–95; n=3761; China | Baseline | 5 years | Baseline | 5 years | Adults living in Zhangwu city had a significantly lower Tg than adults living in Huanghua and Pangshan cities at baseline (p<0.001) and 5 years (p<0.001) | |||
| Panshan | 103 | 97 | Panshan | 7.7 | 11.7 | ||||
| Zhangwu | 375 | 350 | Zhangwu | 6.0 | 9.1 | ||||
| Huanghua | 615 | 635 | Huanghua | 6.4 | 10.2 | ||||
| Bayram et al. (30) | 28.7; n=109; Turkey | 31e | 68.9e | Adults with no goiter had a significantly lower Tg than adults with goiter (p<0.001) | |||||
| Vejbjerg et al. (21) | 18–65; n=4649; Denmark | IS | IS | Adults living in Copenhagen and Aalborg had a significantly lower Tg after introduction of mandatory iodization of salt (p<0.001) | This study included two cross-sectional samples | ||||
| Before | After | Before | After | ||||||
| Copenhagen | 61 | 99 | Copenhagen | 11.5 | 9.1 | ||||
| Aalborg | 45 | 86 | Aalborg | 15.4 | 9.3 | ||||
| Cahoon et al. (72) | 10–33; n=7890; Belarus | NR | UIC (μg/L) | Adults with UIC 100–2120 μg/L had a significantly lower median Tg than subjects with UIC of 50–100, 20–50, and 0–20 μg/L (p<0.001) | |||||
| 0–20 | 12.1 | ||||||||
| 20–50 | 9.7 | ||||||||
| 50–100 | 8.0 | ||||||||
| 100–2120 | 6.6 | ||||||||
Range used unless mean reported.
Only subjects with no known thyroid disease or negative for TgAb.
Median used unless mean or geometric mean reported.
Geometric mean.
Mean.
UIC reported as urinary iodine excretion (μg/day).
UIC reported as μg/g creatinine.
Table 5.
Intervention Studies Investigating the Effect of Iodine Supplementation on Tg in Newborns, Children, and Adults
| Authors | Age (years)a; country | Study designb | UIC (μg/L)c | Tg (μg/L)c | Findings | Comments | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Newborns | ||||||||||||
| Pedersen et al. (85) | Newborns; Denmark | Data obtained from infants (n=54) born to mothers who were randomized to receive either 200 μg I/day or no iodine supplement | 0 μg | 27 | 0 μg | 67 | Infants of mothers supplemented with 200 μg I/day had a significantly lower Tg than infants born to mothers not taking supplements (p=0.005) | A lag period (i.e., 5 days) between the collection of urine from infants and cord blood samples | ||||
| 200 μg | 64 | 200 μg | 38 | |||||||||
| Glinoer et al. (86) | Newborns; Belgium | Data obtained from infants (n=180) born to mothers who were randomized to receive either 131 μg I/day, 131 μg+100 μg L-T4, or placebo | 0 μg | 43d | 0 μg | 113d | Infants of mother supplemented with 131 μg I and 131 μg I+L-T4 had a significantly lower Tg than infants of mothers taking placebo (p<0.001) | Cord blood used | ||||
| 131 μg | 77d | 131 μg | 65d | |||||||||
| 131 μg+L-T4 | 80d | 131 μg+L-T4 | 52d | |||||||||
| Children | ||||||||||||
| Benmiloud et al. (89) | 6–11; Algeria | Children (n=169) randomized to receive either a single dose of iodized poppy seed oil orally (120, 240, 480, or 960 mg I) or intramuscular injection of 480 mg I for 150–395 days | Baseline | 5 months | Baseline | 5 months | All groups of children had a decrease in Tg after 5 months | The study only reported Tg values for baseline and 5 months | ||||
| Orally | ||||||||||||
| 120 mg | 27 | 41 | 98.5 | 31.0 | ||||||||
| 240 mg | 25 | 99 | 98.5 | 22.0 | ||||||||
| 480 mg | 25 | 109 | 175.0 | 24.0 | ||||||||
| 960 mg | 25 | 132 | 77.0 | 14.0 | ||||||||
| Injection | ||||||||||||
| 480 mg | 27 | 1185 | 62.0 | 12.0 | ||||||||
| Zimmermann et al. (47) | 6–15; Morocco | Children (n=377) received IS for 12 months | Baseline | Months | Baseline | Months | Children had a significantly lower Tg after using IS for 12 months (p<0.001) | |||||
| 5 | 12 | 5 | 12 | |||||||||
| 17 | 181 | 165 | 24.5 | 6.2 | 4.4 | |||||||
| Zimmermann et al. (40) | 5–14; Morocco | Children (n=86) received IS for 10 months | Baseline | Months | Baseline | Months | Children had a significantly lower Tg after using IS for 10 months (p<0.001) | |||||
| 5 | 10 | 5 | 10 | |||||||||
| 12 | 74 | 102 | 49.0 | 13.0 | 8.0 | |||||||
| Gordon et al. (64) | 10–13; New Zealand | Children (n=184) randomized to receive either placebo or 150 μg I tablet daily for 28 weeks | Baseline | 7 months | Baseline | 7 months | Children taking iodine tablets had a significantly lower Tg after 7 months (p<0.001) | Main outcome was cognition | ||||
| 0 μg | 62 | 81 | 15.2 | 11.6 | ||||||||
| 150 μg | 66 | 145 | 16.5 | 8.5 | ||||||||
| Adults | ||||||||||||
| Thomson et al. (63) | 60–80; New Zealand | Adults (n=100) randomized to receive either placebo, 100 μg Se, 80 μg I, or 100 μg Se+80 μg I daily for 12 weeks | Baselinee | 3 monthse | Baselinee | 3 monthse | Both groups taking iodine supplements had a significantly lower Tg after 3 months compared to baseline (p<0.01) | |||||
| 0 μg | 49 | 44 | 14.4 | 14.0 | ||||||||
| Se | 45 | 44 | 15.4 | 15.2 | ||||||||
| 80 μg | 33 | 71 | 21.2 | 15.4 | ||||||||
| Se+80 μg | 63 | 84 | 17.3 | 14.7 | ||||||||
| Soriguer et al. (92) | 34.9; Spain | A cross-over study of adults (n=30) randomized to 100, 200, or 300 μg I/day | Baselined,f | 2 monthsd,f | Baselined | 2 monthsd | There was no difference in Tg between the groups after supplementation | A cross-over study with 1 month washout; adults recruited were regular users of IS | ||||
| 100 μg | 192 | 233 | 3.9 | 0.8 | ||||||||
| 200 μg | 140 | 230 | 7.6 | 8.8 | ||||||||
| 300 μg | 201 | 377 | 6.8 | 4.0 | ||||||||
Range used unless mean reported.
Only subjects with no known thyroid disease or negative for TgAb.
Median used unless mean or geometric mean reported.
Mean.
Geometric mean.
UIC reported as urinary iodine excretion (μg/day).
Se, selenium.
Children
Six observational studies measuring Tg in children aged between 5 and 14 years were identified (Table 4). Four studies (30,39,41,73) found that iodine-deficient children had a median Tg ≥13 μg/L (range 13–59 μg/L), while two studies (40,41) reported that iodine-sufficient children also had a median Tg ≥13 μg/L (range 13–19 μg/L). Four of six studies (39–41,55) reported that children with adequate iodine status had a median Tg <13 μg/L. However, one study (39) reported that iodine-deficient children had a median Tg <13 μg/L. The study by Zimmermann et al. (41) included 2512 children from 12 countries with severe iodine deficiency (i.e., median UIC <20 μg/L), mild iodine deficiency (i.e., median UIC 50–99 μg/L), adequate iodine status (i.e., median UIC 100–299 μg/L), and iodine excess (i.e., median UIC ≥300 μg/L). It showed that median Tg appeared to follow a U-shaped curve with the nadir at an UIC of 100–300 μg/L. When iodine intake is very high, excess iodide transiently inhibits the activity of thyroid peroxidase and proteolysis of Tg, which subsequently reduces the synthesis and secretion of thyroid hormones (i.e., the Wolff–Chaikoff effect) (87). However, when prolonged excess iodine intake occurs, Tg could increase because the thyroid gland fails to escape from the Wolff–Chaikoff effect (88). Nonetheless, close examination of data reported by Zimmermann et al. (41) suggests that the relationship between UIC and Tg is highly variable. It is not known, however, how much of this variability is associated with UIC and/or Tg because a single UIC can be confounded by the hydration status, dietary intake, and diurnal variation (4).
Four intervention studies investigating the effect of iodine supplementation on Tg in iodine-deficient children aged 5–14 years for a duration of 5–12 months were identified (Table 5). Three of the four studies (40,47,64) were more than six months long, and reported that median Tg decreased significantly and fell below 13 μg/L when UIC increased from <100 to ≥100 μg/L. The remaining study (89) included five treatment groups but not a control group, was only five months long, and had fewer children in each group. In the three groups where the children became iodine sufficient, Tg was <13 μg/L in only one group.
The majority of observational and intervention studies in school children appear to support the 13 μg/L cutoff proposed by Zimmermann et al. (41) to assess iodine status in this age group. However, the relationship between UIC and Tg is not always consistent, suggesting that Tg alone should not be used to assess iodine status in this group.
Adults
Twelve observational studies measuring Tg in adults aged between 18 and 97 years were identified (Table 4). Seven studies (21,25,30,38,43,45,46) showed that iodine deficient adults had a median Tg ≥13 μg/L (range 16–69 μg/L), while only one study (45) reported that iodine-sufficient adults had a median Tg ≥13 μg/L. However, 8 of 12 studies (21,25,42–44,72,90,91) reported that adults who were categorized as iodine deficient had a median Tg <13 μg/L. One of these studies (42) included adults with iodine excess (i.e., median UIC ≥300 μg/L) who, in contrast to the findings of Zimmermann et al. (41) in schoolchildren, had a median Tg <13 μg/L.
Two intervention studies investigating the effect of iodine supplementation on Tg in adults were identified (Table 5). One study included iodine-sufficient middle-aged adults supplemented with additional iodine for 8–12 weeks (92); at baseline, the median Tg was <13 μg/L, which decreased, but not significantly, after supplementation. Another study of older adults (60–80 years) (63) who were moderately iodine deficient reported a median Tg ≥13 μg/L at baseline. Although iodine status improved, the subjects remained mildly iodine deficient, which likely explains that, although Tg concentration significantly decreased after supplementation, it remained ≥13 μg/L.
Based on these observational studies, it is difficult to conclude that the Tg cutoff of 13 μg/L suggested by Zimmermann et al. (41) for children can be used as a biomarker of iodine status in adults. Furthermore, there are no randomized placebo-controlled trials in adults that have shown an improvement in iodine status (indicated by an increase in baseline UIC from <100 to ≥100 μg/L) results in a concomitant fall in Tg concentration from ≥13 to <13 μg/L.
Summary and Conclusions
Tg does hold promise as a biomarker of iodine deficiency. However, it is also associated with limitations. The variety of methods used to analyze Tg makes it difficult to compare studies. It would be helpful if studies that measured Tg standardized their assays with CRM-457. Furthermore, particularly in adult populations, subjects should be screened for TgAb. Despite these problems, the studies included in this review support the use of Tg as a biomarker of iodine status in school children using the <13 μg/L cutoff as suggested by Zimmermann et al. (41). However, it is not possible to draw conclusions regarding the efficacy of Tg in adults because the data are equivocal, while there are no studies of pregnant women with adequate iodine status that also include data on Tg concentration. In particular, few intervention studies have investigated the diagnostic performance of Tg assays and its clinical relevance in assessing iodine status in healthy populations. Well-designed randomized placebo-controlled trials are required to investigate further the effect of iodine supplementation on Tg in mild to moderately iodine-deficient populations, particularly in adults and pregnant women.
Author Disclosure Statement
The authors declare that they have no conflict of interest.
References
- 1.Zimmermann MB.2009Iodine deficiency. Endocr Rev 30:376–408 [DOI] [PubMed] [Google Scholar]
- 2.Pearce EN, Andersson M, Zimmermann MB.2013Global iodine nutrition: where do we stand in 2013? Thyroid 23:523–528 [DOI] [PubMed] [Google Scholar]
- 3.Nath SK, Moinier B, Thuillier F, Rongier M, Desjeux JF.1992Urinary excretion of iodide and fluoride from supplemented food grade salt. Int J Vitam Nutr Res 62:66–72 [PubMed] [Google Scholar]
- 4.König F, Andersson M, Hotz K, Aeberli I, Zimmermann MB.2011Ten repeat collections for urinary iodine from spot samples or 24-hour samples are needed to reliably estimate individual iodine status in women. J Nutr 141:2049–2054 [DOI] [PubMed] [Google Scholar]
- 5.WHO/UNICEF/ICCIDD 2007 Assessment of Iodine Deficiency Disorders and Monitoring Their Elimination: A Guide for Programme Managers. Third editions. WHO, Geneva [Google Scholar]
- 6.Zimmermann MB, Hess SY, Adou P, Toresanni T, Wegmüller R, Hurrell RF.2003Thyroid size and goiter prevalence after introduction of iodized salt: a 5-y prospective study in schoolchildren in Côte d'Ivoire. Am J Clin Nutr 77:663–667 [DOI] [PubMed] [Google Scholar]
- 7.Zimmermann MB.2008Methods to assess iron and iodine status. Br J Nutr 99:S2–S9 [DOI] [PubMed] [Google Scholar]
- 8.Bourdoux PP.1993Biochemical evaluation of iodine status In: Delange F, Dunn JT, Glinoer D. (eds) Iodine Deficiency in Europe: A Continuing Concern. Plenum Press, New York, pp 119–125 [Google Scholar]
- 9.Lamas L, Anderson PC, Fox JW, Dunn JT.1989Consensus sequences for early iodination and hormonogenesis in human thyroglobulin. J Biol Chem 264:13541–13545 [PubMed] [Google Scholar]
- 10.van de Graaf SA, Ris-Stalpers C, Pauws E, Mendive FM, Targovnik HM, de Vijlder JJ.2001Up to date with human thyroglobulin. J Endocrinol 170:307–321 [DOI] [PubMed] [Google Scholar]
- 11.Torréns JI, Burch HB.2001Serum thyroglobulin measurement: Utility in clinical practice. Endocrinol Metab Clin North Am 30:429–467 [DOI] [PubMed] [Google Scholar]
- 12.Deme D, Gavaret JM, Pommier J, Nunez J.1976Maximal number of hormonogenic iodotyrosine residues in thyroglobulin iodinated by thyroid peroxidase. Eur J Biochem 70:7–13 [DOI] [PubMed] [Google Scholar]
- 13.Song Y, Driessens N, Costa M, De Deken X, Detours V, Corvilain B, Maenhaut C, Miot F, Van Sande J, Many M-C, Dumont JE.2007Roles of hydrogen peroxide in thyroid physiology and disease. J Clin Endocrinol Metab 92:3764–3773 [DOI] [PubMed] [Google Scholar]
- 14.Dunn JT, Anderson PC, Fox JW, Fassler CA, Dunn AD, Hite LA, Moore RC.1987The sites of thyroid hormone formation in rabbit thyroglobulin. J Biol Chem 262:16948–16952 [PubMed] [Google Scholar]
- 15.Lamas L, Dorris ML, Taurog A.1972Evidence for a catalytic role for thyroid peroxidase in the conversion of diiodotyrosine to thyroxine. Endocrinology 90:1417–1426 [DOI] [PubMed] [Google Scholar]
- 16.Kostrouch Z, Bernier-Valentin F, Munari-Silem Y, Rajas F, Rabilloud R, Rousset B.1993Thyroglobulin molecules internalized by thyrocytes are sorted in early endosomes and partially recycled back to the follicular lumen. Endocrinology 132:2645–2653 [DOI] [PubMed] [Google Scholar]
- 17.Nunez J, Pommier J.1982Formation of thyroid hormones. Vitam Horm 39:175–229 [DOI] [PubMed] [Google Scholar]
- 18.de Vijlder JJ, den Hartog MT.1998Anionic iodotyrosine residues are required for iodothyronine synthesis. Eur J Endocrinol 138:227–231 [DOI] [PubMed] [Google Scholar]
- 19.Pezzino V, Vigneri R, Squatrito S, Filetti S, Camus M, Polosa P.1978Increased serum thyroglobulin levels in patients with nontoxic goiter. J Clin Endocrinol Metab 46:653–657 [DOI] [PubMed] [Google Scholar]
- 20.de Vijlder JJ, Ris-Stalpers C, Vulsma T.1999On the origin of circulating thyroglobulin. Eur J Endocrinol 140:7–8 [DOI] [PubMed] [Google Scholar]
- 21.Vejbjerg P, Knudsen N, Perrild H, Laurberg P, Carlé A, Pedersen IB, Rasmussen LB, Ovesen L, Jørgensen T.2009Thyroglobulin as a marker of iodine nutrition status in the general population. Eur J Endocrinol 161:475–481 [DOI] [PubMed] [Google Scholar]
- 22.Ikekubo K, Jutton J, Schneider AB.1980Radioimmunoassay of human thyroglobulin with use of “thyroglobulin-free” plasma prepared by ultracentrifugation as diluent. Clin Chem 26:1566–1568 [PubMed] [Google Scholar]
- 23.Nakamura S, Sakata S, Minamori Y, Komaki T, Kojima N, Kamikubo K, Yasuda K, Miura K.1984Serum thyroglobulin (Tg) concentration in healthy subjects: absence of age- and sex-related differences. Endocrinol Jpn 31:93–98 [DOI] [PubMed] [Google Scholar]
- 24.Pacini F, Pinchera A, Giani C, Grasso L, Doveri F, Baschieri L.1980Serum thyroglobulin in thyroid carcinoma and other thyroid disorders. J Endocrinol Invest 3:283–292 [DOI] [PubMed] [Google Scholar]
- 25.Fenzi GF, Ceccarelli C, Macchia E, Monzani F, Bartalena L, Giani C, Ceccarelli P, Lippi F, Baschieri L, Pinchera A.1985Reciprocal changes of serum thyroglobulin and TSH in residents of a moderate endemic goitre area. Clin Endocrinol (Oxf ) 23:115–122 [DOI] [PubMed] [Google Scholar]
- 26.Mitchell ML, Klein RZ, Sargent JD, Meter RA, Haddow JE, Waisbren SE, Faix JD.2003Iodine sufficiency and measurements of thyroid function in maternal hypothyroidism. Clin Endocrinol (Oxf ) 58:612–616 [DOI] [PubMed] [Google Scholar]
- 27.Izumi M, Larsen PR.1978Correlation of sequential changes in serum thyroglobulin, triiodothyronine, and thyroxine in patients with Graves' disease and subacute thyroiditis. Metabolism 27:449–460 [DOI] [PubMed] [Google Scholar]
- 28.Van Herle AJ, Hershman JM, Hornabrook RW, Chopra IJ.1976Serum thyroglobulin in inhabitants of an endemic goiter region of New Guinea. J Clin Endocrinol Metab 43:512–516 [DOI] [PubMed] [Google Scholar]
- 29.Bayram F, Borazan B, Torun E, Tanrıverdi F, Güven M, Erdoğan N, Muhtaroğlu S, Ünlühızarcı K, Tutuş A, Keleştimur F.2003The prevalence of endemic goiter and iodine deficiency and evaluation of thyroid function in an area of central Anatolia. Turk J Endocrinol Metab 7:37–43 [Google Scholar]
- 30.Bayram F, Beyazyildiz A, Gökçe C, Budak N, Erdoğan N, Kurtoğlu S, Kula M, Ünlühızarcı K, Keleştimur F.2009The prevalence of iodine deficiency, serum thyroglobulin, anti-thyroglobulin and thyroid peroxidase antibody levels in the urban areas of Kayseri, Central Anatolia. Exp Clin Endocrinol Diabetes 117:64–68 [DOI] [PubMed] [Google Scholar]
- 31.Swanson CA, Zimmermann MB, Skeaff S, Pearce EN, Dwyer JT, Trumbo PR, Zehaluk C, Andrews KW, Carriquiry A, Caldwell KL, Egan SK, Long SE, Bailey RL, Sullivan KM, Holden JM, Betz JM, Phinney KW, Brooks SP, Johnson CL, Haggans CJ.2012Summary of an NIH workshop to identify research needs to improve the monitoring of iodine status in the United States and to inform the DRI. J Nutr 142:1175S–1185S [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Black EG, Sheppard MC, Hoffenberg R.1987Serial serum thyroglobulin measurements in the management of differentiated thyroid carcinoma. Clin Endocrinol (Oxf ) 27:115–120 [DOI] [PubMed] [Google Scholar]
- 33.Spencer CA, Wang CC.1995Thyroglobulin measurement: techniques, clinical benefits, and pitfalls. Endocrinol Metab Clin North Am 24:841–863 [PubMed] [Google Scholar]
- 34.Clark P, Franklyn J.2012Can we interpret serum thyroglobulin results? Ann Clin Biochem 49:313–322 [DOI] [PubMed] [Google Scholar]
- 35.Spencer CA, Takeuchi M, Kazarosyan M.1996Current status and performance goals for serum thyroglobulin assays. Clin Chem 42:164–173 [PubMed] [Google Scholar]
- 36.Spencer CA, LoPresti JS.2008Technology insight: measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer. Nat Clin Pract End Met 4:223–233 [DOI] [PubMed] [Google Scholar]
- 37.Andersen SL, Nøhr SB, Wu CS, Olsen J, Pedersen KM, Laurberg P.2013Thyroglobulin in smoking mothers and their newborns at delivery suggests autoregulation of placental iodide transport overcoming thiocyanate inhibition. Eur J Endocrinol 168:723–731 [DOI] [PubMed] [Google Scholar]
- 38.Pedersen KM, Börlum KG, Knudsen PR, Hansen ES, Johannesen PL, Laurberg P.1988Urinary iodine excretion is low and serum thyroglobulin high in pregnant women in parts of Denmark. Acta Obstet Gynecol Scand 67:413–416 [DOI] [PubMed] [Google Scholar]
- 39.Simsek E, Safak A, Yavuz O, Aras S, Dogan S, Kocabay K.2003Sensitivity of iodine deficiency indicators and iodine status in Turkey. J Pediatr Endocrinol Metab 16:197–202 [DOI] [PubMed] [Google Scholar]
- 40.Zimmermann MB, de Benoist B, Corigliano S, Jooste PL, Molinari L, Moosa K, Pretell EA, Al-Dallal ZS, Wei Y, Zu-Pei C, Torresani T.2006Assessment of iodine status using dried blood spot thyroglobulin: Development of reference material and establishment of an international reference range in iodine-sufficient children. J Clin Endocrinol Metab 91:4881–4887 [DOI] [PubMed] [Google Scholar]
- 41.Zimmermann MB, Aeberli I, Andersson M, Assey V, Yorg JA, Jooste P, Jukić T, Kartono D, Kusić Z, Pretell E, San Luis TO, Jr., Untoro J, Timmer A.2013Thyroglobulin is a sensitive measure of both deficient and excess iodine intakes in children and indicates no adverse effects on thyroid function in the UIC range of 100–299 μg/L: a UNICEF/ICCIDD study group report. J Clin Endocrinol Metab 98:1271–1280 [DOI] [PubMed] [Google Scholar]
- 42.Teng W, Shan Z, Teng X, Guan H, Li Y, Teng D, Jin Y, Yu X, Fan C, Chong W, Yang F, Dai H, Yu Y, Li J, Chen Y, Zhao D, Shi X, Hu F, Mao J, Gu X, Yang R, Tong Y, Wang W, Gao T, Li C.2006Effect of iodine intake on thyroid diseases in China. N Engl J Med 354:2783–2793 [DOI] [PubMed] [Google Scholar]
- 43.Rasmussen LB, Ovesen L, Bülow I, Jørgensen T, Knudsen N, Laurberg P, Perrild H.2002Relations between various measures of iodine intake and thyroid volume, thyroid nodularity, and serum thyroglobulin. Am J Clin Nutr 76:1069–1076 [DOI] [PubMed] [Google Scholar]
- 44.Knudsen N, Bülow I, Jørgensen T, Perrild H, Ovesen L, Laurberg P.2001Serum Tg-a sensitive marker of thyroid abnormalities and iodine deficiency in epidemiological studies. J Clin Endocrinol Metab 86:3599–3603 [DOI] [PubMed] [Google Scholar]
- 45.Gutekunst R, Smolarek H, Hasenpusch U, Stubbe P, Friedrich HJ, Wood WG, Scriba PC.1986Goitre epidemiology: thyroid volume, iodine excretion, thyroglobulin and thyrotropin in Germany and Sweden. Acta Endocrinol (Copenh) 112:494–501 [DOI] [PubMed] [Google Scholar]
- 46.Laurberg P, Pedersen KM, Hreidarsson A, Sigfusson N, Iversen E, Knudsen PR.1998Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab 83:765–769 [DOI] [PubMed] [Google Scholar]
- 47.Zimmermann MB, Moretti D, Chaouki N, Torresani T.2003Development of a dried whole-blood spot thyroglobulin assay and its evaluation as an indicator of thyroid status in goitrous children receiving iodized salt. Am J Clin Nutr 77:1453–1458 [DOI] [PubMed] [Google Scholar]
- 48.Hjort T, Friis T, Lauridsen UB, Persson I.1974Thyroglobulin in serum after TSH stimulation in hyperthyroidism. Acta Endocrinol (Copenh) 75:699–706 [DOI] [PubMed] [Google Scholar]
- 49.Torrigiani G, Doniach D, Roitt IM.1969Serum thyroglobulin levels in healthy subjects and in patients with thyroid disease. J Clin Endocrinol Metab 29:305–314 [DOI] [PubMed] [Google Scholar]
- 50.Van Herle AJ, Uller RP, Matthews NI, Brown J.1973Radioimmunoassay for measurement of thyroglobulin in human serum. J Clin Invest 52:1320–1327 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Laurberg P, Pedersen KM.1987A sensitive radio-immunoassay for serum thyroglobulin—including a correct screening for thyroglobulin autoantibodies. Scand J Clin Lab Invest 47:685–689 [PubMed] [Google Scholar]
- 52.Spencer CA, Bergoglio LM, Kazarosyan M, Fatemi S, LoPresti JS.2005Clinical impact of thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas. J Clin Endocrinol Metab 90:5566–5575 [DOI] [PubMed] [Google Scholar]
- 53.Wunderlich G, Zöphel K, Crook L, Smith S, Smith BR, Franke WG.2001A high-sensitivity enzyme-linked immunosorbent assay for serum thyroglobulin. Thyroid 11:819–824 [DOI] [PubMed] [Google Scholar]
- 54.Spencer C, Fatemi S, Singer P, Nicoloff J, Lopresti J.2010Serum basal thyroglobulin measured by a second-generation assay correlates with the recombinant human thyrotropin-stimulated thyroglobulin response in patients treated for differentiated thyroid cancer. Thyroid 20:587–595 [DOI] [PubMed] [Google Scholar]
- 55.Skeaff SA, Lonsdale-Cooper E.2013Mandatory fortification of bread with iodised salt modestly improves iodine status in schoolchildren. Br J Nutr 109:1109–1113 [DOI] [PubMed] [Google Scholar]
- 56.Schlumberger M, Hitzel A, Toubert ME, Corone C, Troalen F, Schlageter MH, Claustrat F, Koscielny S, Taieb D, Toubeau M, Bonichon F, Borson-Chazot F, Leenhardt L, Schvartz C, Dejax C, Brenot-Rossi I, Torlontano M, Tenenbaum F, Bardet S, Bussière F, Girard JJ, Morel O, Schneegans O, Schlienger JL, Prost A, So D, Archambeaud F, Ricard M, Benhamou E.2007Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients. J Clin Endocrinol Metab 92:2487–2495 [DOI] [PubMed] [Google Scholar]
- 57.Feldt-Rasmussen U, Schlumberger M.1988European interlaboratory comparison of serum thyroglobulin measurement. J Endocrinol Invest 11:175–181 [DOI] [PubMed] [Google Scholar]
- 58.Stanojevic M, Savin S, Cvejic D, Djukic A, Jeremic M, Zivancević Simonovic S.2009Comparison of the influence of thyroglobulin antibodies on serum thyroglobulin values from two different immunoassays in post surgical differentiated thyroid carcinoma patients. J Clin Lab Anal 23:341–346 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 59.Zucchelli GC, Pilo A, Masini S, Prontera C, Ferdeghini M.1996Large between-laboratory variability of thyroglobulin immunoassays: data collected in a collaborative study. J Clin Ligand Assay 19:234–238 [Google Scholar]
- 60.Feldt-Rasmussen U, Profilis C, Colinet E, Black E, Bornet H, Bourdoux P, Carayon P, Ericsson UB, Koutras DA, Lamas de Leon L, DeNayer P, Pacini F, Palumbo G, Santos A, Schlumberger M, Seidel C, Van Herle AJ, De Vijlder JJ.1996Human thyroglobulin reference material (CRM 457). 1st part: assessment of homogeneity, stability and immunoreactivity. Ann Biol Clin (Paris) 54:337–342 [PubMed] [Google Scholar]
- 61.Spencer CA.2013Measurement of thyroglobulin In: Braverman LE, Cooper DS. (eds) Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text. Tenth edition. Lippincott Williams & Wilkins, Philadelphia, p 301 [Google Scholar]
- 62.Schulz R, Bethäuser H, Stempka L, Heilig B, Moll A, Hüfner M.1989Evidence for immunological differences between circulating and thyroid tissue-derived thyroglobulin in men. Eur J Clin Invest 19:459–463 [DOI] [PubMed] [Google Scholar]
- 63.Thomson CD, Campbell JM, Miller J, Skeaff SA, Livingstone V.2009Selenium and iodine supplementation: effect on thyroid function of older New Zealanders. Am J Clin Nutr 90:1038–1046 [DOI] [PubMed] [Google Scholar]
- 64.Gordon RC, Rose MC, Skeaff SA, Gray AR, Morgan KM, Ruffman T.2009Iodine supplementation improves cognition in mildly iodine-deficient children. Am J Clin Nutr 90:1264–1271 [DOI] [PubMed] [Google Scholar]
- 65.Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt-Rasmussen U, Henry JF, LiVosli VA, Niccoli-Sire P, John R, Ruf J, Smyth PP, Spencer CA, Stockigt JR.2003Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13:3–126 [DOI] [PubMed] [Google Scholar]
- 66.Pedersen IB, Knudsen N, Jørgensen T, Perrild H, Ovesen L, Laurberg P.2003Thyroid peroxidase and thyroglobulin autoantibodies in a large survey of populations with mild and moderate iodine deficiency. Clin Endocrinol (Oxf ) 58:36–42 [DOI] [PubMed] [Google Scholar]
- 67.Okamura K, Nakashima T, Ueda K, Inoue K, Omae T, Fujishima M.1987Thyroid disorders in the general population of Hisayama Japan, with special reference to prevalence and sex differences. Int J Epidemiol 16:545–549 [DOI] [PubMed] [Google Scholar]
- 68.Spencer CA, Takeuchi M, Kazarosyan M, Wang CC, Guttler RB, Singer PA, Fatemi S, LoPresti JS, Nicoloff JT.1998Serum thyroglobulin autoantibodies: Prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 83:1121–1127 [DOI] [PubMed] [Google Scholar]
- 69.Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE.2002Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 87:489–499 [DOI] [PubMed] [Google Scholar]
- 70.Marwaha RK, Tandon N, Karak AK, Gupta N, Verma K, Kochupillai N.2000Hashimoto's thyroiditis: countrywide screening of goitrous healthy young girls in postiodization phase in India. J Clin Endocrinol Metab 85:3798–3802 [DOI] [PubMed] [Google Scholar]
- 71.Kaloumenou I, Mastorakos G, Alevizaki M, Duntas LH, Mantzou E, Ladopoulos C, Antoniou A, Chiotis D, Papassotiriou I, Chrousos GP, Dacou-Voutetakis C.2008Thyroid autoimmunity in schoolchildren in an area with long-standing iodine sufficiency: correlation with gender, pubertal stage, and maternal thyroid autoimmunity. Thyroid 18:747–754 [DOI] [PubMed] [Google Scholar]
- 72.Cahoon EK, Rozhko A, Hatch M, Polyanskaya O, Ostroumova E, Tang M, Nadirov E, Yauseyenka V, Savasteeva I, McConnell RJ, Pfeiffer RM, Brenner AV.2013Factors associated with serum thyroglobulin levels in a population living in Belarus. Clin Endocrinol (Oxf ) 79:120–127 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73.Skeaff SA, Thomson CD, Wilson N, Parnell WR.2012A comprehensive assessment of urinary iodine concentration and thyroid hormones in New Zealand schoolchildren: a cross-sectional study. Nutr J 11:31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74.Brucker-Davis F, Ferrari P, Gal J, Berthier F, Fenichel P, Hieronimus S.2012Iodine status has no impact on thyroid function in early healthy pregnancy. J Thyroid Res 2012:168764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75.Raverot V, Bournaud C, Sassolas G, Orgiazzi J, Claustrat F, Gaucherand P, Mellier G, Claustrat B, Borson-Chazot F, Zimmermann M.2012Pregnant French women living in the Lyon area are iodine deficient and have elevated serum thyroglobulin concentrations. Thyroid 22:522–528 [DOI] [PubMed] [Google Scholar]
- 76.Laurberg P, Bjarnadottir R, Pedersen KM, Børlum KG, Hreidarsson AB.1994Pregnancy is associated with an increase in s-thyroglobulin independent of iodine deficiency. A comparative study in countries with different levels of iodine intake. J Endocrinol Invest 17:72 [Google Scholar]
- 77.Brough L, Jin Y, Shukri NH, Wharemate ZR, Weber JL, Coad J.2013Iodine intake and status during pregnancy and lactation before and after government initiatives to improve iodine status, in Palmerston North, New Zealand: a pilot study. Matern Child Nutr [Epub ahead of print]; DOI: 10.1111/mcn.12055 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78.Eltom A, Elnagar B, Elbagir M, Gebre-Medhin M.2000Thyroglobulin in serum as an indicator of iodine status during pregnancy. Scand J Clin Lab Invest 60:1–7 [DOI] [PubMed] [Google Scholar]
- 79.Costeira MJ, Oliveira P, Ares S, Roque S, de Escobar GM, Palha JA.2010Parameters of thyroid function throughout and after pregnancy in an iodine-deficient population. Thyroid 20:995–1001 [DOI] [PubMed] [Google Scholar]
- 80.Liesenkötter KP, Göpel W, Bogner U, Stach B, Grüters A.1996Earliest prevention of endemic goiter by iodine supplementation during pregnancy. Eur J Endocrinol 134:443–448 [DOI] [PubMed] [Google Scholar]
- 81.Nøhr SB, Jørgensen A, Pedersen KM, Laurberg P.2000Postpartum thyroid dysfunction in pregnant thyroid peroxidase antibody-positive women living in an area with mild to moderate iodine deficiency: is iodine supplementation safe? J Clin Endocrinol Metab 85:3191–3198 [DOI] [PubMed] [Google Scholar]
- 82.Santiago P, Velasco I, Muela JA, Sánchez B, Martínez J, Rodriguez A, Berrio M, Gutierrez-Repiso C, Carreira M, Moreno A, García-Fuentes E, Soriguer F.2013Infant neurocognitive development is independent of the use of iodised salt or iodine supplements given during pregnancy. Br J Nutr 110:831–839 [DOI] [PubMed] [Google Scholar]
- 83.Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W.2011Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 21:1081–1125 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 84.De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, Eastman CJ, Lazarus JH, Luton D, Mandel SJ, Mestman J, Rovet J, Sullivan S.2012Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 97:2543–2565 [DOI] [PubMed] [Google Scholar]
- 85.Pedersen KM, Laurberg P, Iversen E, Knudsen PR, Gregersen HE, Rasmussen OS, Larsen KR, Eriksen GM, Jøhannesen PL.1993Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation. J Clin Endocrinol Metab 77:1078–1083 [DOI] [PubMed] [Google Scholar]
- 86.Glinoer D, De Nayer P, Delange F, Lemone M, Toppet V, Spehl M, Grün JP, Kinthaert J, Lejeune B.1995A randomized trial for the treatment of mild iodine deficiency during pregnancy: Maternal and neonatal effects. J Clin Endocrinol Metab 80:258–269 [DOI] [PubMed] [Google Scholar]
- 87.Leung AM, Braverman LE.2013Consequences of excess iodine. Nat Rev Endocrinol. doi: 10.1038/nrendo.2013.251 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 88.Scientific Committee on Food 2002 Opinion of the Scientific Commitee on Food on the Tolerable Upper Intake Level of Iodine. SCF/CS/NUT/UPPLEV/26 Final. Health & Consumer Protection Directorate-General, European Commission, Brussels [Google Scholar]
- 89.Benmiloud M, Chaouki ML, Gutekunst R, Teichert HM, Wood WG, Dunn JT.1994Oral iodized oil for correcting iodine deficiency: optimal dosing and outcome indicator selection. J Clin Endocrinol Metab 79:20–24 [DOI] [PubMed] [Google Scholar]
- 90.Hintze G, Windeler J, Baumert J, Stein H, Köbberling J.1991Thyroid volume and goitre prevalence in the elderly as determined by ultrasound and their relationships to laboratory indices. Acta Endocrinol (Copenh) 124:12–18 [DOI] [PubMed] [Google Scholar]
- 91.Thomson CD, Woodruffe S, Colls AJ, Joseph J, Doyle TC.2001Urinary iodine and thyroid status of New Zealand residents. Eur J Clin Nutr 55:387–392 [DOI] [PubMed] [Google Scholar]
- 92.Soriguer F, Gutiérrez-Repiso C, Rubio-Martin E, Linares F, Cardona I, López-Ojeda J, Pacheco M, González-Romero S, Garriga MJ, Velasco I, Santiago P, García-Fuentes E.2011Iodine intakes of 100–300 μg/d do not modify thyroid function and have modest anti-inflammatory effects. Br J Nutr 105:1783–1790 [DOI] [PubMed] [Google Scholar]
- 93.Costeira MJ, Oliveira P, Ares S, de Escobar GM, Palha JA.2009Iodine status of pregnant women and their progeny in the Minho Region of Portugal. Thyroid 19:157–163 [DOI] [PubMed] [Google Scholar]