Introduction
Iodine is an essential micronutrient needed for the synthesis of thyroid hormones triiodothyronine (T3) and thyroxine (T4) and adequate production is required for growth, development, and regulation of the metabolism [
1]. Mild to moderate iodine deficiency is widespread among adults in Europe [
2], including Norway [
3,
4]. Globally, the iodization of table salt is the main strategy to prevent iodine deficiency disorders and iodized salt is the primary dietary source of iodine in countries with mandatory iodine fortification policy [
5]. Norway has not implemented salt iodization and low iodine intake has been reported among women of fertile age, pregnant and breastfeeding women, infants who are exclusively breastfed, elderly, vegans, and immigrants [
4]. In Norway, animal source foods such as cow’s milk and yoghurt, eggs (due to iodine fortification of fodder), and marine fish are the main dietary iodine sources. WHO recommend assessment of median urinary iodine concentration (UIC) as an indicator for iodine status in a population [
5]. In addition to UIC, thyroglobulin (Tg) can also serve as a marker of iodine deficiency and altered thyroid activity. When iodine intakes decrease, iodine stores in the thyroid gland diminish [
6]. Tg, a protein synthesized by the thyroid cells, increases thyroid activity to maintain thyroid hormone concentrations within the normal range [
7,
8].
People adhering to a plant-based diet can be categorized as vegans (no intake of animal source foods) lacto-ovo vegetarian (intake of milk/dairy products, cheese and/or eggs) or pescatarian (intake of milk/dairy products, cheese and/or eggs, in addition to fish/shellfish/fish products). Plant-based diets are typically associated with low iodine intakes compared to omnivore diets [
9], unless iodine-containing supplements or microalgae is consumed. The iodine content in macroalgae may, however, vary widely both between and within species, and some products contain excessive amounts of iodine [
10], and may be an unreliable iodine source [
11]. Plant-based milk and dairy products have low iodine content, unless they are fortified with iodine [
12,
13].
The synthesis of thyroid hormones is catalyzed by thyroid peroxidase (TPO) which uses selenium as a cofactor. Selenium is an essential element that is required for selenocysteine synthesis and production of selenoproteins [
14]. Animal source foods such as dairy products, meat and seafoods have high selenium concentration, and for plant-foods, the concentration of selenium depend on the selenium level in soil. Lower selenium status has been reported in vegetarians and vegans as compared to omnivores in epidemiological studies [
15]. Urine is the main route of excretion of selenium, mainly in the form of selenosugar [
16] and have been considered as a useful marker of recent selenium intake [
17] and a biomarker of selenium status of a population [
18].
Inorganic arsenic has been found to inhibit TPO in vitro and arsenic exposure has been associated with thyroid dysfunction. Arsenic is an element that can exist in various chemical forms, with inorganic arsenic classified as carcinogenic whereas the organic form arsenobetaine is regarded non-toxic, in addition to many chemical forms not yet fully characterized for their toxicity [
19]. In a Norwegian randomized controlled trial, ingestion of seafood rich in total arsenic was associated with an increase in thyroid-stimulating hormone (TSH) [
20]. Most arsenic compounds present in food items are excreted in urine with a half time generally of a few days, and therefore, measurement of total urinary arsenic has been used as a biomarker of arsenic exposure [
21,
22].
Since the most important dietary iodine sources in Norway are found in animal source foods, individuals following a plant-based diet are at particular risk of iodine deficiency [
23], but the impact on thyroid function is uncertain. Thus, the objective of this study is to assess thyroid function and urinary iodine, creatinine, selenium, and arsenic concentration in subjects adhering to a vegan, lacto-ovo vegetarian, and pescatarian diet.
Discussion
A normal thyroid gland can adapt to mild iodine deficiency and maintain thyroid hormone production [
31]. The physiological response involves increased blood Tg concentration and higher thyroid activity [
7]. Since there are no reference values for Tg in adults, we compared differences in Tg between the dietary groups. Vegans had higher Tg concentration compared to pescatarians, indicating that a low iodine intake increase thyroid activity and the thyroid production of Tg. Vegan non-supplement users had higher Tg compared to vegans consuming an iodine-containing supplements, consistent with other studies [
7,
32]. Larger epidemiological studies have shown that prolonged thyroid stimulation associated with such an adaptation leads to thyroid growth, and during follicular cell proliferation, there is a tendency to mutations leading to multifocal autonomous growth and dysfunction [
31,
33]. In populations with mild and moderate iodine deficiency, such multifocal autonomous thyroid function is a common cause of hyperthyroidism [
34], particularly in elderly people, and the prevalence of thyroid enlargement and nodularity is higher than in iodine sufficient populations [
31,
33]. In Denmark, profound effects of even minor differences in iodine intake level on the prevalence of goiter, nodules, and hyperthyroidism have been reported [
35]. However, the incidence of multinodular toxic goiter and thyrotoxicosis decreased with improved iodine intake [
36].
We found a low prevalence of thyroid dysfunction in our study and fT3, fT4 and TSH were within normal ranges. In the Adventist Health Study-2, there was no association between vegan diets and hypothyroidism [
37]. However, in a more recent study focusing on a subsample of the Adventist Health Study-2, Tonstad found that those with elevated TSH (> 5 mUI/L) were more likely to be women following a vegan or vegetarian diet [
38]. Leung et al. conducted a study in 140 vegetarians and vegans in USA and found TSH and FT4 concentrations in the normal range [
39]. Although serum TSH was generally normal in 101 British vegans, mean TSH was 47% higher than for omnivores [
40]. No thyroid function abnormalities were found in Swedish and Finnish vegans [
41,
42].
Median UIC in the participating vegans, lacto-ovo-vegetarians and pescatarians indicated mild- to moderate iodine deficiency. Even in those using iodine supplements, UIC indicated inadequate iodine intake. It might be explained by the fact that iodine supplements with 150 µg iodine/day might not be sufficient in a people adhering to plant-based diets, or it can be challenges related to compliance with iodine supplements. In Norway, the iodine fortification of table salt is voluntary, and the permitted level of iodine is only 5 µg/g salt thus table salt is considered a negligible iodine source in the Norwegian diet [
4]. Ovo-lacto vegetarians and pescatarian have iodine sources such as milk, dairy products, and eggs (fish for the pescatarian). Vegans have few iodine sources in their diet and are dependent on iodine supplements or intake of macroalgae to maintain an adequate iodine intake.
In our study, creatine-adjusted UIC, was higher than UIC. There are two factors that may contribute to this apparent disparity: with no meat intake in the study population, the total amount of creatinine destined for urine excretion (as creatinine) per 24 h may be less than in the general population from where the adjustment equation originates, inflating the creatine-adjusted UIC [
43]. Second, a high urine volume may have diluted the iodine concentration in the spot sample reducing the expected UIC [
6]. The WHO cutoff value for iodine deficiency is, however, not adjusted for creatinine, therefore, we compare UIC in our study with the WHO guidelines. WHO recommend use of spot urine as an easy and cost-efficient method for assessing iodine status in population groups. However, there is large inter- and intra-individual variation in UIC caused by differences in iodine intake as well as by large variation in fluid intake [
5].
The total sample median urinary selenium concentration (13 µg/L) were below the reported levels in the Canadian Health Measures Survey [reference value (RV
95)] of 120 µg/L [
25] and in a Belgian population (RV
95 of 62 µg/L) [
44]. The levels are, however, within the same range as seen in a study of blood and urine of healthy unexposed subjects living in different regions of the United Kingdom, where a reference interval from 6 to 43 µg/L was set for selenium [
45]. The findings of relatively low urinary selenium in our study are also comparable to a study by Fallon [
46], which found low intakes and selenium in women of fertile age adhering to strict plant-based diets. Worldwide selenium intake varies considerably, with populations in Europe having relatively low selenium intake, compared to, e.g., North America and some parts of South America and Asia where selenium content of soil is high [
47]. In this study, no difference was observed in selenium concentration between the different dietary groups. In Norway, fish was recently calculated to contribute with over 20% of the total mean intake of selenium for adults (general population) [
48].
The median urinary concentrations of arsenic (3 µg/L) were low compared to a previous study from Norway where median total arsenic levels in urine were 102 µg/L, ranging from 8 to 859 µg/L [
49]. Median urinary concentrations of arsenic in our study were also lower compared to the European reference populations where mean concentrations of urinary inorganic arsenic and related metabolites were 5–6 µg/L [
27]. Total arsenic comprise of different arsenic species, whereas inorganic arsenic and the simple methylated forms are generally present in urine [
27]. The toxicity of arsenic depends on the chemical form present, with inorganic arsenic being more toxic than organic arsenic compounds, although many compounds not yet fully characterized for their toxicity. Fish and seafood generally contain high levels of total arsenic, whereas the concentration of inorganic arsenic is usually low [
27]. In most seafood, arsenic is mainly present in the form of arsenobetaine, which is assumed to be of no toxicological concern and is excreted unchanged in urine [
27]. According to a risk assessment conducted by European Food Safety Authority (EFSA), Norway was considered the country with highest intake of arsenic in Europe, due to the high consumption of fish [
27]. In Norway, foods with high concentration of inorganic arsenic are rice and rice products, supplements based on algae, and shellfish [
50]. However, cereals and cereal products, vegetables, bottled water, and coffee contribute with the highest intake because they are consumed more frequently or in higher volumes [
28].
Our study adds important data on iodine nutrition and thyroid function in population groups consuming vegan, lacto-ovo vegetarian and pescatarian diets. A strength of this study was the sample size of over 200 participants, compared to previous studies in people following plant-based diets. Another strength is that we measured several indicators of thyroid function and iodine nutrition: thyroid hormones, thyroglobulin, iodine supplement, macroalgae and urinary iodine. Limitations of the study were: lack of reference values for thyroglobulin [
28] and the non-randomized study design, which resulted in smaller sample size in the pescatarian groups. The study also lacked a control group, but we included pescatarian groups which include all the dietary iodine sources in Norway. However, it is still a limitation that we did not include an omnivore group, as pescatarians might differ from the general populations as they might limit the intake of dairy products, eggs, and seafood to more extent.