Iodine and Autoimmune Thyroid

If you’re interested in some of the research that has been done on iodine and autoimmune thyroid diseases, this post covers some of those studies.

Introduction to iodine and its effects

Although adequate iodine consumption is important for thyroid hormone production and iodine deficiency is the most common cause of hypothyroidism worldwide, its supplemental use in autoimmune Hashimoto’s hypothyroidism is contraindicated. Iodine is the major cofactor and stimulator for thyroid peroxidase (TPO), which helps produce thyroid hormone. TPO is also the primary enzyme under attack with Hashimoto’s.

It appears that increased iodine intake, especially as a supplement, increases the immune attack on the thyroid.¹
The extreme of this clinical expression is called the Jod-Basedow Phenomenon², this phenomenon is portrayed as individuals who are iodine-deficient in conjunction with elevated thyroid antibodies.

When these individuals are given exogenous iodine supplements, they develop a hyperfunction autoimmune response. Although this phenomenon does take place in clinical practice at times, iodine supplementation with autoimmune thyroid disorders does not always lead into thyroid hyperfunction. Rather, one observes increased levels of TPO autoantibody levels that multiply dramatically with iodine supplements, and in many instances an increase in thyroid overactive symptoms.

Studies conducted on the effects of iodine addition to table salt

In areas of the world where iodine has been added to sodium chloride (table salt), the rates of autoimmune thyroid have risen.

China

Participants enrolled in a baseline study in 1999, and during the five-year follow-up through 2004, the effect of regional differences in iodine intake on the incidence of thyroid disease was examined.

Method: Of the 3761 unselected subjects who were enrolled at baseline, 3018 (80.2 percent) participated in this follow-up study. Levels of thyroid hormones and thyroid autoantibodies in serum, and iodine in urine, were measured, and B-mode ultrasonography of the thyroid was performed at baseline and follow-up.

Conclusion: More than adequate or excessive iodine intake may lead to hypothyroidism and autoimmune thyroiditis.³

Sri Lanka

A study was conducted to evaluate the evolution of thyroid autoimmunity in relation to the change in goiter prevalence during 3 years of iodine prophylaxis.

Results: The results indicate an evolution of thyroid autoimmune markers during the course of iodine prophylaxis, which has not been described before.⁴

Turkey

A study evaluated the effects of iodine intake on the prevalence of thyroid dysfunction, autoimmunity, and goiter in two regions with different iodine status after two years of iodization.

Study population: In total, 1733 adolescent subjects were enrolled into the study.

Method: They measured:

• free thyroxine (fT4)
• thyrotropin (TSH)
• antithyroid peroxidase antibodies (Anti-TPO)
• antithyroglobulin antibodies (Anti-Tg)
• urinary iodine (UI), and examined the thyroid gland by ultrasound.

Results: The research study concluded that iodine supplementation in Turkey has resulted in the elimination of iodine deficiency in the Eastern Black Sea Region, and this has been accompanied by an increase in the prevalence of autoimmune thyroiditis and thyroid dysfunction.⁵

A study observing;

1.    The effects of iodine on levels of CD4/CD8

Concluded that iodine might exert influence on the level of CD4/CD8, and thus the production of thyroid antibodies might directly or indirectly take part in the process of thyroid autoimmunity.

Both low iodine and 100 times normal iodine intakes might activate the immune state on some degrees.

2.    Production of Thyroglobulin (TG) and Thyroid peroxidase (TPO) antibodies

Concluded that the effects of iodine on immune responses of TG and TPO antigens in thyroid autoimmunity might not be completely the same.⁶[i]

3.    The role of iodine in thyroid autoimmunity

A research study concluded that thyroglobulin polymorphisms, combined with the explosive mix of iodine, TPO Ab, and H2O2 necessary for thyroid hormone synthesis, inadvertently provide the trigger for the autoimmune thyroid response.⁷

A study evaluating the prevalence of chronic Autoimmune thyroiditis (CAT), iodine-induced hypothyroidism, overt and subclinical hyperthyroidism and goiter

Study population: A population exposed to excessive iodine intake for 5 years (table salt iodine concentrations: 40-100 mg/kg salt). This was a population-based, cross-sectional study with 1085 participants randomly selected from a metropolitan area in São Paulo, Brazil, and conducted during the first semester of 2004.

Method:

1. Thyroid ultrasound examination was performed in all participants and samples of urine and blood were collected from each subject.
2. Serum levels of thyroid-stimulating hormone, free thyroxine, and anti-thyroid peroxidase (TPO) antibodies, urinary iodine concentration, thyroid volume, and thyroid echogenicity were evaluated.
3. The study also analyzed table salt iodine concentrations.

Note: At the time the study was conducted, table salt iodine concentrations were within the new official limits (20-60 mg/kg salt). Nevertheless, in 45.6% of the participants, urinary iodine excretion was excessive (above 300 microg/l) and, in 14.1%, it was higher than 400 microg/l.

Results:

1. The prevalence of CAT (including atrophic thyroiditis) was 16.9% (183/1085); women were more affected than men (21.5 vs 9.1% respectively, P=0.02).
2. Hypothyroidism was detected in 8.0% (87/1085) of the population with CAT.
3. Hyperthyroidism was diagnosed in 3.3% of the individuals (36/1085) and goiter was identified in 3.1% (34/1085).

Conclusion: The study concluded that after five years, iodine intake by the Brazilian population may have increased the prevalence of chronic autoimmune thyroid and hypothyroidism in subjects genetically predisposed to thyroid autoimmune diseases. Appropriate screening for early detection of thyroid dysfunction may be considered during excessive nutritional iodine intake.⁸

A study estimating chosen markers of endothelial dysfunction in iodine-induced thyrotoxicosis (IIT)

It has been reported that hyperthyroidism is associated with an altered endothelial function and increased risk of arterial thromboembolism.

Study population: The groups studied consisted of 41 hyperthyroid subjects, who had been treated with amiodarone (n = 6) or vitamin preparations supplemented with iodine (n = 35) and 40 persons with normal thyroid function.

Method: The following parameters were measured:

• Thyroglobulin antibodies (TG Ab)
• Thyroid peroxidase antibodies (TPO Ab)
• THS receptor antibodies (TR Ab)
• Soluble adhesion molecules: sVCAM-1 and sICAM-1,
• Von Willebrand factor (vWF)
• Plasminogen activator inhibitor-1 (PAI-1)
• C-reactive protein (CRP)
• Fibrinogen and urine iodine concentration.

Results:

1. Patients with IIT had significantly higher levels of sVCAM-1 (p < 0.01), IL-6 (p < 0.005), fibrinogen (p < 0.005) and CRP (p < 0.05) in comparison to healthy subjects, whereas sICAM-1, PAI-1 and vWF concentrations did not differ between the groups studied.
2. The highest sVCAM-1 levels were observed in patients with amiodarone induced thyrotoxicosis, and fibrinogen and CRP–in subjects receiving vitamin preparations.
3. There were significant correlations between sVCAM-1 concentration and the levels of sICAM-1 (r = 0.341; p = 0.029) and PAI-1 (r = 0.347; p = 0.026), as well as with urine iodine concentration (r = 0.448; p = 0.004). IL-6 concentration correlated with vWF (r = 0.456; p = 0.003), TPO Ab (r = 0.328; p = 0.036) and PAI-1 level (r = 0.319; p = 0.042).

Conclusion: The study concluded that iodine induced thyrotoxicosis is associated with an increase of sVCAM-1 and IL-6 levels, possibly reflecting inflammatory and destructive processes in the thyroid gland. However, increased procoagulant activity was not found in patients with IIT.⁹

A study accessing the relationship between biological exposure to iodine and hypothyroidism

Study population and method: Logistic regression model was used to analyze the risk factors of hypothyroidism, according to the epidemiologic data of 3761 adults in 3 kinds of rural communities:

• Mild iodine deficiency area (4 natural villages in Panshan County, Liaoning Province)
• More than adequate iodine (7 natural villages of Zhangwu County, Liaoning Province)
• Excessive iodine area (2 natural villages of Huanghua City, Hebei Province).

Conclusion: The study concluded that more than adequate iodine and excessive iodine were independent risk factors of subclinical hypothyroidism (OR = 3.172 and 6.391, P < 0.05) and overt hypothyroidism (OR = 3.696 and 9.213, P < 0.05).

Iodine still a risk-factor: When interactions of iodine exposure and thyroid peroxidase antibody (TPOAb) or thyroglobulin antibody (TgAb) were included, more than adequate iodine was still a risk factor of subclinical hypothyroidism (OR = 2.788, P < 0.01), but had no such effect on overt hypothyroidism. Interaction of more than adequate iodine and positive TgAb significantly affected subclinical hypothyroidism and overt hypothyroidism (OR = 2.656 and 3.347, P < 0.05).

Summary: More than adequate and excessive iodine exposure are independent risk factors of hypothyroidism. The risk of hypothyroidism goes up and thyroid dysfunction becomes more serious with the increasing biological exposure to iodine.¹⁰

A study Investigating the current iodine status and the impact of silent iodine prophylaxis on the prevalence of autoimmune thyroiditis among school children in North Western Greece.

The findings were compared to those obtained from a similar survey conducted 7 years previously in the same area.

Study population: A total of 302 school children (12-18 years of age) from a mountainous area of northwestern Greece were examined for the presence of goiter, and blood and urine samples were collected for assessment of thyroid function, antithyroid antibodies and urinary iodine excretion.

Method: In those children (n = 42) with palpable goiter or positive antibodies and/or a thyrotropin (TSH) level greater than 5 mU/L, thyroid ultrasonography was performed to estimate thyroid gland size and morphology.

Results:

1. Median urinary iodine concentration in the children was 20.21 microg/dL, indicating sufficient iodine intake.
2. Thyroid function was normal in all but 7 children, who had subclinical hypothyroidism (2.5%).
3. Antithyroid antibodies (antithyroid peroxidase [TPO] and/or antithyroglobulin [Tg]) were positive in 32 children, including those with subclinical hypothyroidism (10.6%).
4. Twenty-nine of these children (9.6%) also had the characteristic echo pattern of thyroiditis on ultrasound and were diagnosed to have autoimmune thyroiditis.
5. In comparison to data from our previous survey 7 years ago, there has been a threefold increase in the prevalence of autoimmune thyroiditis among school children.

Conclusion: Silent iodine prophylaxis resulted in the elimination of iodine deficiency in Greece, and this has been accompanied by an increase in the prevalence of autoimmune thyroiditis.¹¹

Similar study on school children in mountainous areas of Azerbaijan

Study background: The school children suffer from severe Iodine Deficiency (ID) with median Urinary Iodine Excretion (UIE) 36 mcg/l and prevalence of goiter 99% (estimated by US).

Study population: 293,000 school children aged 8-14 y.o.,

Method: Administration of capsules containing 190 mg of iodized oil (Lipiodol-Guerbet, Cedex, France) twice yearly in 6 months apart (total 380 mg).

The aim of the present study: To evaluate the efficacy, the benefits, as well as the possible side-effects in a follow-up period of 6 and 12 months after the initial administration of iodized oil.

Six and 12 months after the initial administration of iodide, two representative samples of 391 and 326 children respectively were examined.

The evaluation included:

• estimation of goiter by US,
• determination of UIE and serum measurements of T3, T4, TSH, Tg, autoantibodies against thyroid peroxidase (anti-TPO) and
• thyroglobulin (anti-Tg).

Results:

1. There was an improvement in median UIE, which increased from 36 mcg/l to 68 and 81 mcg/l after 6 and 12 months of treatment respectively.
2. The prevalence of goiter decreased from 99% to 54% and 26% respectively.
3. Tg was decreased at 6 and 12 months from the first administration, whereas TSH remained unchanged at 6 months and decreased at 12 months when compared to the latter value.
4. Hypothyroidism was detected in 7% of children after iodide administration both at 6 and 12 months, but overt hypothyroidism was observed only in 0.5% at 12 months.
5. Subclinical hyperthyroidism was detected in 2% and 6% after iodide administration both at 6 and 12 months.
6. There was a significant increase in the title of thyroid autoantibodies in 6 months, which was retained and increased in 12 months.
7. There was no relation between the appearance of thyroid dysfunction and the positive thyroid autoantibodies.

Conclusion: It was concluded that the dose of 190 mg iodine administered twice yearly, improved iodine deficiency and endemic goiter in school children.

The increase of UIE resulted from iodide administration, was accompanied by an increased title of thyroid auto-antibodies and an increased prevalence of hyper and hypo-thyrotropinemia apparently of no autoimmune etiology.¹²

Lifelong thyroid hormone replacement is indicated in patients with hypothyroidism as a result of Hashimoto’s thyroiditis.

However previous reports have shown that excess iodine induces hypothyroidism in Hashimoto’s thyroiditis.

A study investigating the effects of iodine restriction on the thyroid function and the predictable factors for recovery in patients with hypothyroidism due to Hashimoto’s thyroiditis.

Sample population: The subject group consisted of 45 patients who had initially been diagnosed with hypothyroidism due to Hashimoto’s thyroiditis.

The subjects were divided randomly into two groups:

1. One group was an iodine intake restriction group (group 1) (iodine intake: less than 100 micro g/day)
2. The other group was an iodine intake non-restriction group (group 2).

Method: The thyroid-related hormones and the urinary excretion of iodine were measured at the baseline state.

Results: After 3 months, a recovery to the euthyroid state was found in 78.3 % of group 1 (18 out of 23 patients), which is higher than the 45.5% from group 2 (10 out of 22 patients).

• In group 1, mean serum fT4 level (0.80 +/- 0.27 ng/dL at the baseline, 0.98 +/- 0.21 ng/dL after 3 months) and the TSH level (37.95 +/- 81.76 micro IU/mL at the baseline, 25.66 +/- 70.79 micro IU/mL after 3 months) changed significantly during this period (p < 0.05).
• In group 2, the mean serum fT4 level decreased (0.98 +/- 0.17 ng/dL at baseline, 0.92 +/- 0.28 ng/dL after 3 months, p < 0.05). In the iodine restriction group, the urinary iodine excretion values were higher in the recovered patients than in non-recovered patients (3.51 +/- 1.62 mg/L vs. 1.21 +/- 0.39 mg/ L, p=0.006) and the initial serum TSH values were lower in the recovered patients than in the non-recovered patients (14.28 +/- 12.63 micro IU/mL vs. 123.14 +/- 156.51 micro IU/mL, p=0.005).

Conclusion: 78.3% of patients with hypothyroidism due to Hashimoto’s thyroiditis regained an euthyroid state iodine restriction alone. Both a low initial serum TSH and a high initial urinary iodine concentration can be predictable factors for a recovery from hypothyroidism due to Hashimoto’s thyroiditis after restricting their iodine intake.¹³

A study on the effect of iodine on autoimmune thyroiditis

What is autoimmune thyroiditis?

It is an organ-specific autoimmune disorder characterized by infiltration of the thyroid gland by lymphocytic inflammatory cells, often followed by hypothyroidism due to destruction and replacement of the follicular tissue.

Various studies done:

Dr. Noel Rose and members of his laboratory at Johns Hopkins University have continued to study autoimmunity using autoimmune thyroiditis as a model. Autoimmune thyroiditis is multifactorial, with both genetic and environmental factors involved.

We have studied familial association of thyroid antibodies in juveniles with either autoimmune thyroiditis or Graves’ disease. Epitope analysis of thyroglobulin autoantibodies showed that autoantibodies from unrelated patients with disease had greater similarity of epitope binding than members of their own family.

Subclass analysis of thyroglobulin autoantibodies indicated that IgG2 was dominant in autoimmune thyroiditis.

Much of our work focused around iodine as an environmental trigger of autoimmune thyroiditis. We showed that iodination of the human thyroglobulin molecule alters its immunoreactivity.

We explored the role of excess iodine ingestion in exacerbating thyroiditis using the NOD.H2h4 mouse as a model.

Results: We found multiple effects of excess iodine, including changing the immunogenicity of the thyroglobulin molecule and the upregulation of ICAM-1 and ROS in the thyrocyte itself.

Summary: These observations may help to delineate the mechanisms by which iodine exacerbates thyroiditis and to explain differences in the host response of genetically susceptible individuals compared to those who are resistant to disease.¹⁴

Citations

1. SurksM, Sievert R. Drugs and thyroid function. NEJM, 1995;333(25):1688.
2. Weetman A. Graves’ Disease. NEJM 2000;343(17):1236.
3. Effect of iodine intake on thyroid disease in China. N Engl J Med. 2006 Jun 29;354(26):2783-93.
4. Evolution of thyroid autoimmunity during iodine prophylaxis0the Sri Lankan experience. Eur J Endocrinol. 2003 Aug;149(2)103-10.
5. High prevalence of thyroid dysfunction and autoimmune thyroiditis in adolescents after elimintion of iodine deficiency in the Eastern Black Sea Region of Turkey. Thyroid 2006 Dec;16(12):1265-71.
6. Experimental study on effects of iodine deficiency and excess on thyroid autoimmunity. Zongua Yu Fang Xue Za Zhi. 2006 Jan;40 (1):18-20.
7. Why measure thyroglobulin autoantibodies rather than thyroid peroxidase autoantibodies? Thyroid 2004 Jul;14(7):510-20.
8. Camargo RY, Tomimoria Ek, Neves Sc, et al. Thyroid and the environment: exposure to excessive nutritional iodine increases the prevalence of thyroid disorders in Sao Paulo, Brazil. Eur J Endocrinol. 2008 Sep;159(3):293-9.
9. Zonenberg A, Tolejko B, Scelachowska M, et al. Markers of endothelial dysfunction in patients with iodine induced hyperthyroidism. Endokryonol Pol. 2006 May-Jun;57(3):210-7.
10. Chong W, Shit Xg, Teng WP, et al. Multifactor analysis of relationship between the biological exposure to iodine and hypothyroidism. Zhongua Yi Za Zhi. 2004 Jul 17:84(14):1171-4.
11. Zois C, Stavrou I, Kalogera C, et al. High prevalence of autoimmune thyroiditis in school children after elimination of iodine deficiency in northwestern Greece. Thyroid. 2003 May;13(5):485-9.
12. Markou KB, Georgopoulous NEA, Makri M, et al. Improvement of iodine deficiency after iodine supplementation in school children of Azerbaijan was accompanied by hypo and hyperthyrotropinemia and increased title of thyroid autoantibodies. J Endocrinol Invest. 2003;26(2 Suppl):43-8.
13. Yoon SJ, Choit SR, Kim DM, et al. The effect of iodine restriction on thyroid function in patients with hypothyroidism due to Hashimoto’s thyroiditis. Yonsi Med J. 2003 Apr 30;44(2):227-35.
14. Lynne Burek C. Autoimmune thyroiditis research at Johns Hopkins University. Immunol Res. 2010 Jan 20. [Epub ahead of print]