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Amy Floreen: Graves Disease and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization 

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Amy Floreen: Graves Disease and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization 

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1) Why is this study important: After reviewing this weeks module material I was interested in the association between autoimmune thyroid diseases and autoimmune gastrointestinal diseases. This study was important because it assessed the relationship between Graves disease (GD) and Inflammatory bowel diseases (IBD), considering causal factor potentials. It specifically considered Ulcerative colitis and Crohn's disease in the context of Graves disease.

2) Identify one key finding of this study and describe how it relates to nutritional sciences. Genetically predicted IBD may increase the risk of GD by 24% . Crohn disease (CD) may increase the risk of GD, whereas ulcerative colitis (UC) may prevent patients from developing GD. Conversely, genetically predicted GD may slightly increase the risk of CD. This correlation may suggest that nutritional interventions for clients experiencing GD and/or CD may benefit from dietary modifications utilized for both disease processes. For example, clientele with GD may benefit from nutrient dense options as tolerated to manage risk of weight loss, Vit D and Calcium supplementation to mitigate bone loss risk, and elimination diets to assess tolerance risks for proinflammatory foods and common irritant foods.

3) What are the clinical implications of this study? More research is needed to identify underlying mechanisms and common autoimmune pathways that may be targeted for future treatment recommendations.

Xian W, Wu D, Liu B, et al. Graves Disease and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization. The Journal of Clinical Endocrinology & Metabolism. Published online December 2, 2022. doi:10.1210/clinem/dgac683

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Graves Disease and Inflammatory Bowel Disease A Bidirectional Mendelian Randomization

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Andrea Ballinger: Effect of Pregnancy on Graves' Disease Rebound after successful remission 

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Andrea Ballinger: Effect of Pregnancy on Graves' Disease Rebound after successful remission 

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One point during this week's module that I found both particularly horrifying and simultaneously fascinating, was the fact that pregnancy is a risk factor for developing Graves' Disease. To supplement my curiosity, I found an article that aimed to show the impact of pregnancy and the postpartum period in facilitating a relapse of hyperthyroidism in patients that were in remission after a course of antithyroid drugs. The study found that of patients that completed their course of ATD and entered remission, a significant rate of relapse was observed in patients that soon after underwent a pregnancy. Additionally, greater than 95% of the relapse cases were observed during the postpartum period (4-8 months/24 months), and not during the first trimester of gestation. Based on these results, the authors recommend patients check their thyroid functions 3-6 months after delivery.

The study did not control for diet at any point of gestation nor during the postpartum time frame. Because such a large percentage of women relapsed during the postpartum period, it would be extremely useful to complete an additional study in which pregnant women in GD remission follow a specific diet, or follow a strict supplement regiment to see what impact this has on continued remission vs relapse rates.

Mario Rotondi, Carlo Cappelli, Barbara Pirali, Ilenia Pirola, Flavia Magri, Rodolfo Fonte, Maurizio Castellano, Enrico Agabiti Rosei, Luca Chiovato, The Effect of Pregnancy on Subsequent Relapse from Graves’ Disease after a Successful Course of Antithyroid Drug Therapy, The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 10, 1 October 2008, Pages 3985–3988, https://doi.org/10.1210/jc.2008-0966

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Graves' disease (GD) is aggravated in early pregnancy, ameliorates in the second half of gestation, and often reexacerbates in the postpartum (PP) ( 1- 3). Studies aimed at identifying possible predictive factors for the PP aggravation of Graves' hyperthyroidism showed that, among all GD patients undergoing pregnancy, those experiencing a thyrotoxic phase in early pregnancy are at higher risk of developing severe hyperthyroidism in the PP period ( 2). The medical treatment of Graves' hyperthyroidism with thionamides (methimazole or propylthiouracile), although effective in reestablishing euthyroidism, is associated with a high rate of relapsing hyperthyroidism once these drugs are discontinued ( 4, 5). In the majority of cases, relapses of hyperthyroidism occur between 6 months and 2 yr after discontinuation of antithyroid drugs (ATD), but long-term relapses may also occur after this period ( 4). Despite these discouraging results, a consistent percentage (nearly 30%) of Graves' patients will enter a prolonged remission after ATD. Thus, medical treatment still remains a valid therapeutic option in GD ( 1, 3).

Normal pregnancy is associated with profound changes of the immune system, which largely influence the clinical activity of autoimmune diseases ( 6- 8). It is known that during pregnancy a shift to a type 2 polarized cytokine profile occurs, which minimizes the maternal cell-mediated immune response against the fetus ( 7). These changes allow maintaining the fetal-maternal allograft, which is not rejected despite diverse paternal histocompatibility antigens ( 9). These pregnancy-induced changes result in a down-regulation of the Th1-mediated effector arms of the immune system, which sustain the clinical remission observed during pregnancy in most patients with autoimmune thyroid disease (AITD) ( 7). On the other hand, the PP period is characterized by a rebound reaction which, accounts for the aggravation of AITD during the puerperium ( 10, 11). The PP-rebound immunity, which is characterized by a Th2 to Th1 return shift, is considered to be responsible for the reactivation of not only AITD but also other Th1-dependent autoimmune disease, such as rheumatoid arthritis ( 12- 15).

The role played by the PP-rebound of immunity, on both the de novo occurrence of GD and the clinical course of GD in patients treated with ATD, have been previously investigated ( 16- 18). However, little is known on the effect played by pregnancy and the PP period in patients with GD, who are in remission after ATD.

The aim of this study was to evaluate the effect of pregnancy and/or the PP period in driving a clinical relapse of hyperthyroidism in GD patients who were in remission after ATD.

Patients and Methods

Patients

The study group encompassed female patients who received a diagnosis of GD in our outpatient clinics between 2000 and 2005. Inclusion criteria were: 1) female patients experiencing GD in their child-bearing age; 2) availability of a reproductive history, including the number of full-term pregnancies before the diagnosis of GD and throughout the study span; 3) completion of a full course (at least 12 months) of methimazole (MMI) treatment with restoration of euthyroidism, as assessed by normal serum levels of free T ₄, free T ₃, and TSH; and 4) remission of Graves' hyperthyroidism, as assessed by clinical and biochemical euthyroidism, lasting for at least 6 months after withdrawing ATD.

A total number of 214 GD patients fulfilled the above criteria. All patients were Caucasians. Their median age and range was 32 (19-43) yr. Hyperthyroid GD and relapsing Graves' hyperthyroidism were diagnosed by measuring the serum concentrations of free T ₄, free T ₃, and TSH and searching for circulating thyroid antibodies (antithyroglobulin, antithyroperoxidase, and anti-TSH receptors antibodies). An ultrasound scan of the thyroid gland was performed in all patients and was consistent with a diagnosis of GD, including evidence of an increased thyroid blood flow. Thyroid scintiscan was performed in doubt cases to rule out destructive thyroiditis. The child-bearing age was defined, taking into account the age of the youngest (19 yr) and oldest (43 yr) woman with GD, who experienced a successful pregnancy. The PP period was defined as 1 yr after delivery. To evaluate the role of pregnancy and the PP period in precipitating a relapse of hyperthyroidism, two groups of patients were constituted: group I encompassed 189 patients, who did not undergo pregnancy after stopping MMI treatment. Group II encompassed 25 patients, who had at least one successful pregnancy after stopping MMI. The mean age was significantly greater ( P = 0.0001) in group I (32.1 ± 5.3 yr), compared with group II (27.3 ± 5.8 yr). To balance the two groups for the age factor, patients in group I were stratified according to their age at diagnosis and, starting from the oldest one, they were excluded from the study until a nonsignificant difference was reached for the mean age between patients in groups I and II. After this procedure, the final group I encompassed 125 patients with GD who did not have a pregnancy after stopping MMI treatment. GD patients were treated with ATD for a median time of 17.5 (12-120) months. The length of the surveillance period, including patients who experienced a relapse of hyperthyroidism, was 16 (6-360) months.

Informed consent, concerning the future use of clinical-pathological data for research purposes, is routinely obtained from all patients attending our clinics. This study was in accordance with the Institution Ethics Committee on human experimentation.

Statistical analysis

Statistical analysis was performed using SPSS software (SPSS, Inc., Evanston, IL). Between-group comparisons were performed by means of Student t test for unpaired data and Mann-Whitney U test according to a normal or a nonparametric distribution of the variable tested. Frequencies among groups were compared by χ ² test with Fisher's correction, when appropriate. To test the effects of different variables independently of a covariate, binary logistic regression analysis was used and partial correlation coefficients were computed. P < 0.05 was considered statistically significant.

Results

Clinical data of patients with GD, subdivided into two groups according to the occurrence of a pregnancy during the follow-up period, are shown in Table 1. In detail, the two groups did not significantly differ in age, duration of treatment with MMI, and total follow-up time. A significantly shorter time to relapse after ATD withdrawal characterized women in group I.

As shown in Fig. 1, a statistically significant difference for the relapse rate between patients in groups I and II was observed. Indeed, a relapse of Graves' hyperthyroidism was observed in 70 of 125 patients in group I (56.0%) and 21 of 25 patients in group II (84.0%; P < 0.05).

To further evaluate the effect of pregnancy in precipitating a relapse of hyperthyroidism in GD patients being euthyroid after ATD, multiple regression analysis was used. A logistic regression model was constructed by entering the relapse/nonrelapse as the dependent dichotomic variable, whereas age, positive family history for AITD, duration of treatment with ATD, number of pregnancies at diagnosis, and number of pregnancies after ATD withdrawal were entered as covariates. The results shown in Table 2 indicate that only the number of pregnancies after ATD withdrawal was significantly related to the occurrence of relapsing hyperthyroidism. The specificity of this finding was confirmed by the lack of any significant effect of the number of pregnancies at the first diagnosis of GD. To discriminate the role of pregnancy and the PP period as a risk factor for relapsing hyperthyroidism, the timing of the relapse was further evaluated in patients of group II. None of these patients experienced a relapse of hyperthyroidism during gestation. In 20 of 21 patients (95.2%), a relapse of Graves' hyperthyroidism occurred in the PP period (between 4 and 8 months after delivery). In only one of 21 women (4.8%), relapsing hyperthyroidism occurred after the PP period (24 months after delivery). In only four of 59 patients who remained in remission throughout the study span (6.8%), a pregnancy was recorded after MMI withdrawal.

Discussion

In our series of female patients with GD, the overall relapse rate of hyperthyroidism after ATD treatment was 60.1%. A significantly higher rate of relapsing hyperthyroidism was found in patients who underwent a pregnancy after stopping ATD, as opposed to patients who did not become pregnant. It is important to note that in none of these patients, relapsing hyperthyroidism occurred during the first trimester of gestation. By contrast, in more than 95% of women who became pregnant after ATD withdrawal and experienced a relapse of GD, hyperthyroidism developed in the PP period. Furthermore, no significant association between the number of successful pregnancies at diagnosis of GD and the occurrence of relapsing hyperthyroidism after ATD was found by multiple regression analysis. Taken together, these findings indicate that the PP period, rather than pregnancy itself, plays a major role in promoting a relapse of hyperthyroidism in GD patients being in remission after ATD treatment.

The fact that the PP period, rather than pregnancy itself, favors the relapse of Graves' hyperthyroidism makes sense according to our current knowledge of the changes in the immune system associated with the PP period, which have been described in the introductory text.

The design of the current study has some limitations because it was a retrospective one, whereas a prospective longitudinal study would be more appropriate for assessing the impact of pregnancy on the relapse of Graves' hyperthyroidism in patients successfully treated by ATD. In the current study, the influence of age at diagnosis of GD, which was previously reported to be negatively related to a worse outcome after ATD treatment ( 19, 20), was tested using a multivariate logistic regression model. This analysis showed a nonsignificant influence of the age factor on relapsing Graves' hyperthyroidism. However, a case-control study with an age-matching criterion between patients with and without a successful pregnancy after ATD withdrawal would be helpful to further rule out the effect of age. Thyroid volume, serum levels of free thyroid hormones, and titers of anti-TSH receptor antibodies, previously reported to influence the rate of successful ATD treatment ( 5, 19), were not taken into account in the present study.

Two clinical recommendations stem from our findings. First, thyroid function should be carefully monitored in female patients with GD who undergo a pregnancy while being in remission after ATD treatment. This would be in line with the most recently published guidelines on the treatment of thyroid dysfunction in pregnancy, which suggest evaluating thyroid function at 3 and 6 months after delivery in those women who are at risk for postpartum thyroiditis ( 2). On the basis of our results, it seems reasonable to behave similarly in Graves' patients by evaluating serum thyroid function parameters and anti-TSH receptors antibodies at 3 and 6 months after delivery. Second, definitive treatment with thyroidectomy or radioiodine should be strongly considered in female patients with GD who plan to become pregnant in the following years.

In conclusion, these results indicate that the PP period is significantly associated with a relapse of hyperthyroidism in GD patients being in remission after ATD. We therefore recommend that patients with GD in remission after a course of ATD should have their thyroid function tested at 3 and 6 months after delivery.

Acknowledgments

The experiments reported in this paper were supported in part by the Progetto di Ricerca Finalizzata ex art. 12, del D.Lgs.502/92-2005.

Disclosure Statement: The authors have nothing to disclose.

Abbreviations

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Effect of Pregnancy on Subsequent Relapse from Graves' Disease after a Successful Course of Antithyroid Drug Therapy

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Graves' disease (GD) is aggravated in early pregnancy, ameliorates in the second half of gestation, and often reexacerbates in the postpartum (PP) ( 1- 3). Studies aimed at identifying possible predictive factors for the PP aggravation of Graves' hyperthyroidism showed that, among all GD patients undergoing pregnancy, those experiencing a thyrotoxic phase in early pregnancy are at higher risk of developing severe hyperthyroidism in the PP period ( 2).

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Thyroid Dysfunction in Relation to Immune Profile, Disease Status, and Outcome in 191 Patients with COVID-19

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Thyroid Dysfunction in Relation to Immune Profile, Disease Status, and Outcome in 191 Patients with COVID-19

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Emalee Haynes

https://doi.org/10.1210/clinem/dgaa813

This article focused on the prevalence of thyroid dysfunction and worsening of thyroid disease in the presence of COVID-19. This study is important because it highlights some long-term effects of coronavirus which are not well known due to the newness of this infection. The result of this study found that, “there may be a direct effect of SARS-CoV-2 on thyroid function, potentially leading to exacerbation of pre-existing autoimmune thyroid disease.” Patients having any kind of thyroid dysfunction will impact their nutritional choices and results. COVID-19 is prevalent, and we are constantly learning new things about it, which is why knowing the potential effects on the thyroid following infection is important. The clinical implications of this study besides general awareness could be obtaining blood work following infection to determine if any changes have occurred within the body in general and related to thyroid functioning. Knowing this risk factor is important when treating patients in any capacity because it can offer suggestions for counseling or treatment choices.

Source: Lui DTW, Lee CH, Chow WS, Lee ACH, Tam AR, Fong CHY, Law CY, Leung EKH, To KKW, Tan KCB, Woo YC, Lam CW, Hung IFN, Lam KSL. Thyroid Dysfunction in Relation to Immune Profile, Disease Status, and Outcome in 191 Patients with COVID-19. J Clin Endocrinol Metab.

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Dierra Doaks

I found a paper that discusses the skin findings in patients with thyroid diseases. The paper talks about how the skin shows the best range of clinical signs of thyroid disease. The researchers started a study to detect the skin findings associated with the diseases. The study involved 220 patients with various thyroid diseases including autoimmune hyperthyroidism, non-autoimmune hyperthyroidism, autoimmune hypothyroidism, non-autoimmune hypothyroidism, autoimmune euthyroidism, and non-autoimmune euthyroidism. The study also involved 90 healthy individuals as a control group. The most frequent skin findings in the patients were chronic urticaria, vitiligo, diffuse alopecia, acne vulgaris, and acne rosacea. Chronic urticaria, vitiligo, and pruritus were significantly higher in the patient group with thyroid diseases compared to the control group. This paper is important because it notes that there is no other report investigating the skin findings among thyroid diseases. This information in the paper could provide valuable data for future research.

ArtantaA, SoLen et al. “Skin Findings in Thyroid Diseases.” European journal of internal medicine 20.2 (2008): 158–161. Web.

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Impact of Drinking Water Fluoride on Human Thyroid Hormones: A Case- Control Study

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Impact of Drinking Water Fluoride on Human Thyroid Hormones: A Case- Control Study

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-Clarisa Williams

Kheradpisheh, Z., Mirzaei, M., Mahvi, A. H., Mokhtari, M., Azizi, R., Fallahzadeh, H., & Ehrampoush, M. H. (2018). Impact of drinking water fluoride on human thyroid hormones: a case-control study. Scientific reports, 8(1), 1-7.

This week I chose to gather information on drinking water and the impact the consumption has on the thyroid. The researchers aimed to study the impact that drinking water fluoride has on TSH, T3, and T4 hormones. There is fluoridation of many water systems across the world. Studying the connection between amount of fluorinated water consumption and thyroid hormone levels can provide a greater understanding of fluorides impact on risk for thyroid dysfunction. One of the key finding of this study addressed TSH levels and higher consumption of fluoride drinking water. This is related to  nutritional sciences because water is an essential nutrient and in the case of thyroid dysfunction, awareness of water consumption is often recommended.  Greater consumption of the drinking water that contained fluoride, even lower in concentration of fluoride, was seen with higher TSH values.  These results were found in individuals without thyroid disease along with individuals with hypothyroidism that was untreated. Making a recommendation for individuals with a greater risk or health history of hypothyroidism to add a purification process to the drinking water could reduce the increase of TSH with lower consumption of fluoride.

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Efficacy of the Autoimmune Protocol Diet as Part of a Multi-disciplinary, Supported Lifestyle Intervention for Hashimoto’s Thyroiditis

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Efficacy of the Autoimmune Protocol Diet as Part of a Multi-disciplinary, Supported Lifestyle Intervention for Hashimoto’s Thyroiditis

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This study is important since Hashimoto’s thyroiditis is the leading cause of hypothyroidism. It focuses on the implementation of the Autoimmune Protocol (AIP) diet and lifestyle change in order to decrease symptoms of hypothyroidism and improve thyroid function in these patients. The goal of the AIP diet was to decrease inflammation and better regulate the immune system. This study found that there was a decrease in inflammatory markers in the patients white blood cell counts. This relates to nutritional studies because the AIP diet is the reason for this change in the body. There are not many treatments for those with HT, besides thyroid hormone replacements, so this could potentially aid patients who do not want this therapy. This can be beneficial clinically because it could potentially be used in HT treatment, as well as treatments for other autoimmune disorders.
Abbott, R. D., Sadowski, A., & Alt, A. G. (2019). Efficacy of the Autoimmune Protocol Diet as Part of a Multi-disciplinary, Supported Lifestyle Intervention for Hashimoto's Thyroiditis. Cureus, 11(4), e4556. https://doi.org/10.7759/cureus.4556

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Joe Devine: Prevalence of hyperthyroidism according to type of vegetarian diet

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Joe Devine: Prevalence of hyperthyroidism according to type of vegetarian diet

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This paper is based on a longitudinal study of seventh day adventists that looked at types of diet against certain health disorders. The study showed that vegan and vegetarian diets were protective against autoimmune diseases, including hyperthyroidism, however modified vegetarian diets were not protective. Since the group in the study adhered to a strict no smoking and no alcohol protocol due to church beliefs these common aggravators of disease were not reported. Some of the hypothesis as to why these diets may be protective range from lower BMI, but also that lower concentrations of leptin in the blood and insulin control may be contributing factors.

Tonstad, S., Nathan, E., Oda, K., & Fraser, G. E. (2014). Prevalence of hyperthyroidism according to type of vegetarian diet. Public Health Nutrition, 18(8), 1482–1487. https://doi.org/10.1017/s1368980014002183

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Zinc Deficiency Associated with Hypothyroidism: An Overlooked Cause of Severe Alopecia

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Zinc Deficiency Associated with Hypothyroidism: An Overlooked Cause of Severe Alopecia

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Ellen Reusch

For this week's wall, I found an article discussing zinc deficiency and its link to hypothyroidism and alopecia. Hypothyroidism often causes hair loss (alopecia), and zinc is one of the elements required for thyroid hormone synthesis, so a deficiency in zinc could lead to a deficiency in thyroid hormone (hypothyroidism). Thyroid hormones are also important for proper absorption of zinc within the human body, so hypothyroidism might also lead to a zinc deficiency, making the relationship between the two very interesting. This particular study set out to see if hypothyroidism supplemented with zinc was beneficial for patients in regards to the severity of their alopecia. The article describes one patient who presented with several complaints (weakness, anorexia, alopecia) who underwent hair testing and thyroid function testing. Her TSH was elevated but T3 and T4 were both below normal limits. The rest of the tests were all normal. The patient started thyroid hormone supplementation, but did not experience any improvement in her symptoms/complaints. Once her zinc level was tested, it was found to be low and she was started on zinc supplements. About a month later, the patient noticed marked improvement in her symptoms. Although this study only reports on one patient, I think it is important to look further into the relationship between zinc supplementation and alopecia in patients with hypothyroidism. This study could lead to further research projects within the endocrinology community and could potentially lead to beneficial outcomes for patients suffering from these conditions. It brings out the importance of not only zinc supplementation, but the need for zinc in our regular everyday diets, which would be one item of conversation for physicians to discuss with their hypothyroidism patients.

Citation: A Betsy, MP Binitha, S Sarita. Zinc Deficiency Associated with Hypothyroidism: An Overlooked Cause of Severe Alopecia. International Journal of Trichology. 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746228/

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Zinc Deficiency Associated with Hypothyroidism: An Overlooked Cause of Severe Alopecia

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Hypothyroidism is a common and well recognized cause of diffuse hair loss. Zinc and other trace elements such as copper and selenium are required for the synthesis of thyroid hormones, and deficiency of these can result in hypothyroidism. Conversely, ...

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Food Consumption with Hashimoto's Disease

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Food Consumption with Hashimoto's Disease

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This week, I picked an article that looks at what types of food individuals with Hashimoto's Thyroiditis (HT) consume compared to "Healthy" (meaning they have no type of thyroid disease) individuals, or the control group. It also compared the types of food consumed by individuals with HT undergoing LT4 therapy, versus individuals with HT that are not undergoing the treatment. In order to collect this information, they used a Food Frequency Questionnaire (FFQ) containing 51 different food items. They found that individuals with HT consumed more nuts, processed meats, and animal fat than the control group. On the other hand the control group consumed more whole grains, red meat, plant oil, and non-alcoholic beverages. While consuming alcoholic beverages wasn't necessarily linked to all individuals with HT, the study did find that patients undergoing LT4 therapy consumed a significant amount more than the individuals not receiving the therapy. A limitation of this study is that it only used qualitative dat, making it difficult to establish a causal relationship.
This study is important, and relates to nutritional sciences, because it attempts to find a difference in food consumption between individuals with HT and individuals without. This was one of the first studies to compare the consumption of foods across such a large cohorts, which could help lead to further research on what dietary intakes are best for them. A clinical implication of this study would be that an FFQ could be beneficial in evaluating a patients diet. While it is not quantitative data, it gives us an idea of what the individuals regular diet might look like, making it easier to determine diet adjustments.

Kaličanin, D., Brčić, L., Ljubetić, K. et al. Differences in food consumption between patients with Hashimoto’s thyroiditis and healthy individuals. Sci Rep 10, 10670 (2020). https://doi.org/10.1038/s41598-020-67719-7

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Introduction

Environmental factors, in addition to genetic factors, play important role in Hashimoto's thyroiditis (HT) development1. HT is a chronic autoimmune thyroid disorder (AITD) characterized by the production of thyroid autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb)2. Other main characteristics of HT include infiltration of lymphocytes and ruination of thyroid tissue, which usually leads to hypothyroidism3. This disease predominantly affects female population and is considered as one of the most frequent endocrine disorders4. The estimated incidence of HT is 350/100,000 for females and 80/100,000 per year for males5. It is most often diagnosed in women between the age of 30 and 606.

High iodine intake (median urinary iodine concentration ≥ 300 μg/L)7, especially in areas with sufficient iodine supply, is one of the most known factors that increase the incidence of HT8. Also, low vitamin D levels (below 30 ng/mL)9 and low selenium intake (bellow 40 µg/day)10 are proposed to be risk factors for HT development, albeit a role of these factors in HT still needs to be confirmed. Conversely, alcohol intake was proposed to decrease the risk for HT11. Other dietary factors are also considered as potential environmental modifiers of the clinical appearance of HT12,13,14,15. A diet low in gluten has been recently proposed to have beneficial effects on the disease course in a study of 34 women with HT13. Another study of 83 patients with HT indicated that restriction of lactose intake in lactose-intolerant HT patients resulted with decreased thyroid-stimulating hormone (TSH) levels14. However, the current knowledge of this topic is scarce and only the following two studies analyzed the association between thyroid function and dietary factors using food frequency questionnaire (FFQ) as an assessment tool to date. A large population-based study of 65,981 participants found an association of the vegan diet with a lower risk of self-reported hypothyroidism16. Another recent study showed that higher animal fat and butter intake are associated with the risk of positivity to TPOAb and/or TgAb antibodies using 1,887 participants, whereas diet rich in vegetables, dried fruit, nuts and muesli consumption decreased that risk17.

The first goal of our study is to identify specific food groups, assessed by FFQ, that differ in consumption frequency between patients with HT and control subjects. Our second goal is to perform a comprehensive set of analyses to test associations of diet with the wealth of HT-related phenotypes and symptoms. Our third goal is to exploit if HT patients change their diet upon HT diagnosis. The overall aim of our study is to contribute to the knowledge related to diet and HT and may be of relevance to nutritionists, nutritional therapists and clinicians involved in developing dietary recommendations for HT patients.

Methods

Study participants

Our study investigated 924 individuals from the region of Split (Southern Croatia), including 491 HT cases and 433 control participants. All procedures have been established according to guidelines of the most relevant thyroid societies (ATA, ETA, Croatian thyroid society). Patients were recruited from the Outpatient clinic for thyroid disorders at the University Hospital Split in the period from 2013 to 2017 and are a part of the Croatian Biobank of patients with Hashimoto's thyroiditis (CROHT)18. The study involved newly diagnosed patients along with patients on follow up. Diagnosis was made by a clinical specialist in nuclear medicine primarily based on clinical examination and thyroid ultrasound. Only individuals with echographic pattern of diffuse thyroid disease (unhomogenous thyroid tissue with diffusely reduced echo levels) were included in the study. Diagnosis of HT was further complemented by evaluation of biochemical measurements. HT was confirmed by at least one of the laboratory parameters falling out of referent ranges: increased TSH and/or decreased thyroid hormones [total triiodothyronine (T3), total thyroxine (T4), free thyroxine (fT4)] and/or increased TPOAb and TgAb autoantibodies. Hormones (TSH, T3, T4, fT4) and levels of thyroid antibodies (TgAb and TPOAb) were measured from the plasma of participants by immunoassay using the fully automated "Liaison" Biomedica Chemiluminescence Analyzer (DiaSorin, Saluggia, Italy). We used the following reference values for hormones and thyroid antibodies levels that are valid for our population: TSH (0.3-3.6 mUI/L), T3 (1.3-3.6 nmol/L), T4 (57.4-161 nmol/L), fT4 (10.1-22.3 pmol/L), TPOAb (1-16 IU/mL), TgAb (5-100 IU/mL). Thyroid ultrasonography was performed using the Medison Accuvix V10 (Samsung Medison Co. Ltd, Seoul 135-280, Korea) high frequency linear probe (8-12 MHz). Thyroid volume was calculated as a sum of volumes of both lobes, where the volume of each lobe was calculated as length × width × depth × 0.47919. The body surface area (BSA) in m ² was calculated as W 0.425 × H 0.725  × 0.007184, where W is the weight (kg) and H the height (cm).

Our HT cases include 289 HT patients without LT4 therapy and 177 HT patients who are taking LT4 therapy (information on LT4 therapy was not available for 25 HT patients). HT patients without LT4 therapy had median TSH levels just above the upper referent values and T3 and T4 levels in normal ranges, indicating that these patients were newly diagnosed or in follow-up care with preserved thyroid function. HT patients with LT4 therapy had median TSH, T3 and T4 levels within the reference ranges, suggesting that their LT4 supplementation was appropriate. Median TgAb/TPOAb levels were increased (above referent values) in both sub-groups of patients. Clinical and sociodemographic characteristics of HT cases are shown in Table 1. A large number of phenotypes was collected from each patient, of which the other relevant ones for this study are: systolic and diastolic blood pressure and the presence/absence of the most common 16 symptoms of hypothyroidism, chosen on the basis of clinical expertise and the data from the literature (weakness, increase in weight, constipation, sensitivity to coldness, cold skin, dry and rough skin, pale skin, loss of skin hair, fragile hair, edema of the eyes, face edema, peripheral edema, harsh voice, slow speech, dyspnea and memory disturbance)20,21.

Table 1 Clinical and sociodemographic characteristics of 491 HT patients and 433 control participants.

Control participants were derived from the population-based "10,001 Dalmatians project" cohort that is a part of the Croatian Biobank program with a large phenotype information on study participants22. We selected individuals from the region of Split to match the origin of HT cases. We used all available self-reported phenotype information to exclude individuals from controls that have HT or any other type of thyroid disorder, such as Graves' disease, thyroid cancer, non-autoimmune hypothyroidism or individuals that used drugs for any type of thyroid disorder. We also used available laboratory measures on thyroid hormones levels (T3, T4, TSH) to keep only individuals whose hormone values fall within the reference range for our population. Finally, we excluded from controls all individuals with positivity to TPOAb (TPOAb level > 16 IU/mL) or TgAb (TgAb level > 100 IU/mL). In this way, we strengthened our control group by minimizing the possibility of having individuals with undiagnosed AITD or any other type of thyroid disorder. Clinical and sociodemographic characteristics of controls are shown in Table 1.

Written informed consent was obtained from all study participants. The study was approved by Ethics Committees from the University of Split, School of Medicine (Classification no. 003-08/14-03/0001; Registry no. 2181-198-03-04-14-0028) and University Hospital Split (Classification no. 530-02/13-01/11; Registry no. 2181-147-01/06/J.B.-14-2). Both Ethics Committees declared that the study is in accordance with the provisions of the Code of Ethics and the Helsinki Declaration.

Assessment of dietary intake

The FFQ is the most commonly used dietary assessment tool for the evaluation of food consumption and measurement of long-term food intake23. Dietary intake of HT patients was assessed using the FFQ that consisted of 51 items concerning foods and beverages. The frequency of intake of each food item was measured using six categories: every day, 2-3 times a week, once a month, once a week, rarely, and never. Participants reported the frequency of consummation of specific food but did not quantify the amount of consumed food (servings). Dietary intake in control participants was assessed using the FFQ that consisted of 54 items regarding foods and beverages. The frequency of food intake was measured using five categories: every day, 2-3 times a week, once a week, rarely, and never. Additionally, there was a question in both FFQs regarding fat consumption with three choices (plant oil, olive oil, and animal fat) and three frequency categories (always, sometimes, and never). Prior analysis, we grouped 48 food items that were common in both questionnaires into 22 food groups (SI Table S1) and we converted the frequency categories into weekly intake for each of the 48 food items (SI Table S2). Our FFQ was not designed to quantify daily intake of nutrients from the food groups.

Statistical analysis

We performed a case-control analysis to identify specific food groups that differ in consumption frequency between HT cases and controls. Specifically, we assessed the association between weekly intake of 22 food groups and HT by using a logistic regression model, where case/control status was used as the dependent variable and 22 food groups as independent variables, along with age and gender.

We also investigated if two sub-groups of HT patients (depending on LT4 therapy) differ in dietary habits, as this analysis is important for data interpretation. The rationale behind this analysis was to take into consideration possible changes in diet between these two sub-groups (for example, HT patients who were taking LT4 therapy might have changed dietary habits upon disease diagnosis) which could introduce spurious associations for our main case-control analysis. We used a logistic regression model, where therapy status (with/without LT4 therapy) was used as the dependent variable and 22 food groups as independent variables, along with age and gender.

We also tested the association between weekly intake of 22 food groups and HT-related quantitative traits (TSH, T3, T4, fT4, TgAb, TPOAb, thyroid volume, systolic blood pressure, and diastolic blood pressure) using a linear regression model, where a selected quantitative trait was the dependent variable and 22 food groups were independent variables. Normality of distribution of residuals was tested using Kolmogorov-Smirnov test while homogeneity of variance was tested using Levene's test. In each model, we included age, gender, and physical activity (the calculation of physical activity is shown in SI Table S3) as covariates and, depending on a quantitative trait, we included additional covariates: body surface area (BSA) and TSH (for association of food groups with thyroid volume, systolic and diastolic blood pressure), BSA (for the association analysis of food groups with TSH and fT4). Analyses were performed in all HT patients and in the two sub-groups depending on LT4 therapy status. In the group comprising all HT patients, we also included LT4 therapy status as an additional covariate, whereas in the sub-group of HT patients that were on LT4 therapy we included both LT4 therapy dose and the weight ratio as an additional covariate. We considered p values corrected for 9 tests ( p  < 0.0056) as statistically significant.

Finally, we assessed the association between 22 food groups and 16 symptoms of hypothyroidism in the sub-group of HT patients without LT4 therapy. For each symptom, we used a logistic regression model where symptom status (with/without symptom) was used as the dependent variable and food groups as independent variables. Age, gender, physical activity, body mass index (BMI) and TSH levels were also included as covariates. The p value corrected for 16 symptoms of hypothyroidism ( p  < 0.0031) was considered statistically significant. All statistical analyses were performed using the Statistical Package Software for Social Science, version 16 (SPSS Inc., Chicago, IL, USA).

Results

The logistic regression analysis revealed that animal fat [OR 1.55 (1.30-1.86), p < 0.0001], processed meat [OR 1.16 (1.06-1.27), p = 0.0012] and nuts [OR 1.23 (1.08-1.40), p = 0.0015] were significantly more frequently consumed in HT patients than in controls, whereas red meat [OR 0.80 (0.72-0.89), p < 0.0001], non-alcoholic beverages [OR 0.82 (0.75-0.89), p < 0.0001], whole grains [OR 0.82 (0.76-0.89), p < 0.0001], plant oil [OR 0.87 (0.82-0.93), p < 0.0001], olive oil [OR 0.90 (0.84-0.96), p = 0.0018], liquor [OR 0.49 (0.29-0.84), p = 0.0087], oily fish [OR 0.72 (0.54-0.96), p = 0.0245] and fruits [OR 0.93 (0.87-0.996), p = 0.0389] were significantly less frequently consumed in HT patients than in control participants (Fig. 1, SI Table S4). Distribution of intakes in both groups is shown in SI Table S4 as a mean weekly intake for each food group.

Comparison of weekly intake frequency for 22 food groups between HT patients and controls. Food groups that were more frequently consumed in HT patients than in controls have odds ratios (OR) above 1, whereas food groups with OR below 1 were less frequently consumed in HT patients. If the OR and the lower limit of the 95% confidence interval (CI) were above 1, the food group was significantly more frequently consumed in HT patients than in controls (bolded and marked with *), whereas if the OR and the upper limit of the 95% CI were below 1, the food group was significantly less frequently consumed in HT patients than in controls (bolded and marked with **). Food groups are ordered from the highest to the lowest OR in both subgroups.

Additionally, our comparison of intake of 22 food groups between HT patients with LT4 therapy and HT patients without LT4 therapy revealed that two sub-groups of HT patients showed no differences in dietary habits except for red meat consumption where patients on LT4 therapy consumed significantly more red meat than HT patients without LT4 therapy [OR 1.24 (1.08-1.43), p = 0.003] (Fig. 2, SI Table S5).

Comparison of weekly intake of 22 food groups between 177 HT patients who were on levothyroxine (LT4) therapy and 289 HT patients without LT4 therapy. Food groups that were more frequently consumed in HT patients on LT4 therapy than in HT patients without LT4 therapy have odds ratios (OR) above 1, whereas food groups with OR below 1 were less frequently consumed in HT patients on LT4 therapy. If the OR and the lower limit of the 95% confidence interval (CI) were above 1, the food group was significantly more frequently consumed in HT patients on LT4 therapy than in HT patients without LT4 therapy (bolded and marked with *). Food groups are ordered from the highest to the lowest OR in both subgroups.

Linear regression analysis between weekly intake of 22 food groups and HT-related phenotypes detected a significant positive association between plant oil consumption and T3 levels in the group including all HT patients (β = 0.07, p < 0.0001) and in the sub-group of HT patients that were on LT4 therapy (β = 0.10, p = 0.001). We also found a negative association between the consumption of olive oil and systolic blood pressure in the sub-group of HT patients that were taking LT4 therapy (β = − 0.16, p = 0.001). All other close-to-significant observations are reported in SI Table S6.

The logistic regression between 22 food groups and 16 symptoms of hypothyroidism showed that food groups, in general, are not associated with symptoms in HT patients without therapy. The only exception was our observation of a significant positive association between the consumption of fruit and constipation [OR 1.38 (1.12-1.70), p = 0.002]. All other close-to-significant observations are listed in SI Table S7.

Discussion

As dietary habits may play a role in HT disease development13,14,15, we performed a set of analyses to detect food groups that: (a) differ between HT patients and controls and (b) may be associated with clinical aspects of HT. We found animal fat, processed meat and nuts, as more frequently consumed food groups in HT patients than in controls. Conversely, red meat, non-alcoholic beverages, whole grains, plant oil, olive oil, liquor, oily fish, and fruits were less frequently consumed in HT patients than in controls. Furthermore, this study detected a positive association between plant oil consumption and T3 levels in HT patients and a negative association between olive oil consumption and systolic blood pressure in the sub-group of HT patients that were on LT4 therapy. Another interesting observation of this study is the lack of association between the 16 symptoms of hypothyroidism with food groups, with the exception of the positive association between fruit consumption and constipation in the group of HT patients without LT4 therapy. Finally, we do not observe that patients with LT4 therapy are prone to change their diet due to disease presence. In the text below, we will discuss observed significant associations according to food group.

Food groups that are more frequently consumed in HT patients

Animal fat

The most significant result of our study was observation of significantly increased consumption of animal fat in HT patients in comparison to controls (Fig. 1, SI Table S4). It is important to have in mind that by animal fat we consider fat that is used in cooking/preparing meals excluding all other fat that can be consumed through red meat or other meat products. This result is in line with and could be considered as replication of the result of the recent population-based study of 1887 participants from south Croatia that found association of animal fat consumption with increased TPOAb and/or TgAb positivity17, key characteristics of HT2. Triglycerides in animal fats, mainly contain saturated (SFA) and monounsaturated fat acids (MUFA)24,25,26. It is known that SFAs may induce development and affect progression of many chronic diseases through inflammatory response27. Two recent studies showed that high-fat diet causes thyroid dysfunction in rats and also induces hypothyroidism by decreasing total T4 and fT4 with increasing TSH levels28,29. These studies suggested that excess intake of animal fat contributes to pathogenesis of hypothyroidism. Our results are in line with these studies, although this result should not be taken as a suggestion to restrict animal fat consumption until further interventional studies are performed.

Processed meat

Processed meat in our study (bacon, sausages and salami) consists mostly of fat, then proteins and in very small amount carbohydrates25,26. Other ingredients of processed meat include nitrates and nitrites, which are used as additives for curing meat products, together with sodium30. A recent systematic review on animal studies showed that high exposure to dietary nitrate or nitrite induces histomorphological changes in thyroid tissue and a decrease in serum levels of thyroid hormones31. It is suggested that high exposure to nitrate/nitrite could inhibit iodine uptake by binding to the sodium-iodide symporter on the surface of thyroid follicles32,33.

Nuts

We believe that increased consummation of nuts in HT cases may be false positive finding. We base this statement on the recently observed trend of increased nut consumption in the city of Split34,35, from which both of our cohorts (HT patients and controls) were derived. More specifically, a comparison of daily nuts consumption between two population-based cohorts from Split, one recruited in 2008-2009 and the other in 2012-2013, showed an increase in nuts consumption from 7 to 11%, respectively34,35. Our control group was formed from the former population-based study whereas our HT case cohort was formed during 2015-2016. Therefore, an observed increase of 2.3% in nuts consumption between HT cases and controls in our study may purely reflect the generally established trend of increase in nut consumption in our population. It is important to state that our FFQ did not distinguish between different types of nuts (raw, salted, roasted). Due to all abovementioned reasons, the interpretation of results regarding nuts is difficult and should be taken with caution.

Food groups that are less frequently consumed in HT patients

Red meat

Red meat is a good source of selenium36, iron, and zinc37, which are essential for the normal function of thyroid hormone synthesis38. Additionally, red meat is rich in vitamin B1237 whose deficiency is associated with AITD39. Unlike processed meat, fresh red meat contains less fat25,26 and does not have additives (nitrites, nitrates and sodium). However, for the purposes of our analyses, red meat included several types of meat (pork, veal, beef, lamb and internal organs) that may contain various amounts of animal fat, which is a limitation factor for interpretation of results. An important remark, we have compared intake of food groups between two sub-groups of HT patients (those with and without LT4 therapy) and found unequal red meat consumption (Fig. 2, SI Table S5), however, both groups of patients still consume less red meat than controls, thus excluding a potential spurious result.

Non-alcoholic beverages

We also found that HT patients consumed significantly less frequently non-alcoholic beverages. Of these, participants most frequently consumed a domestic fruity flavored multivitamin instant drink called Cedevita that contains 9 vitamins (vitamin C, E and B complex: B1, B2, B3, B5, B6, B9 and B12) in 50% of recommended daily allowances (RDA). There is literature record of vitamin deficiencies (vitamin C, A, D and B complex) in patients with thyroid diseases. An anti-inflammatory diet, rich in vitamins and minerals, is recommended as a diet therapy for HT40,41. Additionally, recent study showed that vitamin C intake in AITD patients results in significant lowering of TPOAb antibodies42.

Whole grains

Whole grains are rich in dietary fibers, source of energy for cecum and colon-residing microbiota that metabolize complex carbohydrates and also produce short-chain fatty acids (SCFAs), which are all important for metabolism, cell proliferation and immune system43. Consumption of whole grains, and gluten-rich refined grains, was significantly higher in controls than in HT cases. This is an important observation because it does not support the proposition that a gluten free diet is beneficial to HT patients, as is usually recommended44,45. In line with these results, a recent study showed that muesli consumption, which consists mainly of whole grains46 was associated with a decreased risk of positivity to TPOAb or TgAb antibodies17. Further large randomized studies are needed to give a conclusive answer about effects of gluten reduction in HT patients.

Plant oil

Plant oil, especially cold pressed oil, such as sunflower oil, pumpkin seed oil, and olive oil are rich in bioactive components (polyunsaturated fatty acids (PUFA), tocopherols and various phenols) that are associated with anti-inflammatory properties and reduction of oxidative stress47. Sunflower oil, the most frequently used type of refined plant oil in Croatia, is a natural source of powerful antioxidant vitamin E48.

Olive oil

Olive oil, rich in phenols and oleic acid, was suggested as a dietary factor that may induce clinical benefits in some autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis49,50. Oleocanthal is a natural anti-inflammatory compound from extra virgin cold pressed olive oil that has ibuprofen-like activity51. In fact, many studies have reported anti-inflammatory and immunomodulatory effects from the regular consumption of olive oil52,53,54.

Liquor

Moderate alcohol consumption was already proposed to decrease the risk for HT, which is also in line with our results55.

Oily fish

Oily fish consumption or supplementation with omega-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may reduce inflammation and are of clinical relevance for various autoimmune disorders56,57,58,59. Importantly, a recent study reported an association between omega-3-rich oily fish intake and decreased serum thyroid autoantibodies levels during pregnancy and suggested dietary prophylaxis against thyroid-related postpartum problems60. Oily fish and other seafood are also good source of selenium, iodine, iron and zinc25,61 which are known that could play a beneficial role on a AITD62,63.

Fruits

Finally, beside already mentioned beneficial roles of vitamins, minerals and dietary fibers, fruits additionally contain phytochemicals such as polyphenolic compounds that are known for their anti-inflammatory and antioxidant effects on human health64.

Dietary recommendations

In this paragraph, we briefly discuss our main findings with respect to dietary recommendations. A limitation is that we can discuss our results in the light of the frequency of food intake and not the quantity of intake. According to National dietary guidelines for Croatia65, as our main resource, and United States66 (Mediterranean-Style Eating Pattern), a lower intake of animal fat and processed meat is identified as healthy eating patterns. Although animal fat is rarely consumed in HT patients (mean weekly intake value 0.9, SI Table S4) it is still consumed over 50% more frequently (OR 1.55) than in control participants (mean value 0.5). Processed meat is also not commonly consumed food, in both studied groups, but it is still consumed more often in HT cases. Recommendations for daily consummation of nuts are not reached in both groups. Red meat consummation is within the recommended intake of 3-4 servings per week in both groups. Consummation of liquor is within recommendations in both groups. Lower consummation of non-alcoholic beverages is recommended, and while we do observe uncommon intake of non-alcoholic beverages in both groups, consummation is higher in controls. Importantly, food groups that are recommended for consummation on daily basis, such as whole grains, plant oil, olive oil and fruits, are consumed more often in controls, albeit without reaching recommendations. Finally, recommendations for oily fish consummation of at least once per week are reached in controls but not in HT cases.

Association between food group consumption and clinical aspects of HT

We observed a significant positive association between plant oil consumption and T3 levels in all HT patients and in the sub-group of HT patients that were on LT4 therapy. Our observation may be of particular relevance to HT patients, especially those with more pronounced thyroid dysfunction and requires further confirmation. This observation is also in line with the results of our case-control analyses, as discussed above.

We also observed a significant negative association between olive oil consumption and systolic blood pressure in the sub-group of HT patients that were on LT4 therapy. It was found that hypothyroid individuals have elevated 24-h systolic blood pressure in comparison with individuals without diagnosed hypothyroidism67. A consumption of olive oil was previously shown to be associated with a reduction of systolic blood pressure in hypertensive and healthy individuals68,69. In sum, our study observes that olive oil intake may be associated with positive health outcomes by two lines of evidence: increased consumption in controls and a negative association with systolic blood pressure in HT patients.

Another important result of this study is the lack of association between food groups and 16 symptoms of hypothyroidism20,21 that were assessed in the group of HT patients without LT4 therapy indicating that food consumption does not affect reported symptoms in HT patients. The exception was an observation of a positive association between fruit consumption and constipation. Although fruit consumption is regularly associated with decreased constipation70,71, we found the contradictory result. A possible explanation is that patients with constipation increased their fruit intake to prevent constipation symptoms. The same explanation has already been found and reported in one study72.

This study has several weaknesses that should be mentioned. This is a cross-sectional, observational study that is not designed to give a causal connection between the consumption of food groups and HT development73. Future interventional trials may provide the final conclusion on the causality of the observed associations of food groups and HT. For the same reason, our results should not be taken as a straightforward suggestion for changing dietary habits in HT patients. Another limitation includes the difficulty to accurately measure food-intake consumption in large cohorts. In addition, our FFQ was not designed to collect quantitative data on dietary intake, therefore we were not able to perform quantitative daily assessment of food intake and to calculate nutrient composition. An additional limitation of this study is relevant to the analysis of the association between dietary patterns and 16 symptoms of hypothyroidism. Our questionnaire was designed to collect information on the presence/absence of 16 symptoms of hypothyroidism20,21, but not to collect information on symptom severity. The information on symptom severity would potentially refine the analysis of the effects of food on symptoms of hypothyroidism. On the other hand, the advantages of our study are that we used a large study group of stringently diagnosed HT patients with measures for many clinically-relevant phenotypes. Also, we carefully selected our control group to avoid analysis of control participants with any thyroid dysfunction. To our knowledge, this is the first study that has investigated differences in food consumption between HT patients and control participants.

In conclusion, we have performed the first study that exploits differences in consumption of food groups between large cohorts of HT patients and controls. Our main findings include observation of increased consumption of animal fat and processed meat in HT patients, but also an increased consumption of several food groups (red meat, non-alcoholic beverages, whole grains, plant oil, olive oil, liquor, oily fish and fruits) in controls. Our study also showed that HT patients are not prone to change their diet upon disease diagnosis, as we have found that two sub-groups of HT patients (depending on LT4 therapy) have no main differences in dietary habits, except for red meat consumption. None of the scientific societies have made dietary recommendations for patients with HT, yet these are highly awaited and still need to be developed. Our study contributes to this aim and increases the, currently limited, knowledge related to diet and HT. Our findings may be of particular relevance to nutritional therapists and clinicians involved in treatment of patients with HT.

Data availability

All data is available from the corresponding author upon reasonable request.

Acknowledgements

HT patients were recruited from the "Genome-wide association analysis of Hashimoto's thyroiditis" project funded by the Croatian Science Foundation-HRZZ (Grant no. 4950). The authors thank Shelly Pranić, MS, from the University of Split School of Medicine for language editing of the manuscript.

Author information

Affiliations

1. Department of Medical Biology, University of Split School of Medicine, Soltanska 2, 21000, Split, Croatia

Dean Kaličanin, Luka Brčić, Tatijana Zemunik & Vesna Boraska Perica

2. Department of Clinical Nutrition, Faculty of Health Studies, University of Rijeka, 51000, Rijeka, Croatia

Katija Ljubetić

3. Department of Nuclear Medicine, University Hospital Split, 21000, Split, Croatia

Ana Barić, Sanda Gračan, Marko Brekalo, Vesela Torlak Lovrić & Ante Punda

4. Department of Public Health, University of Split School of Medicine, 21000, Split, Croatia

Ivana Kolčić & Ozren Polašek

Contributions

V.B.P. conceived the study idea; O.P. and I.K. formed the biobank "10,001 Dalmatians", D.K., L.B., A.B., T.Z., A.P and V.B.P formed the biobank of patients with Hashimoto's thyroiditis (CROHT), S.G., M.B. and V.T.L. performed the measurements and diagnosis of H.T., L.B. performed the statistical analysis, D.K., L.B., K.L. and V.B.P. drafted the manuscript, K.L., A.B., T.Z. and A.P. reviewed the manuscript. All authors reviewed the results and approved the final manuscript.

Corresponding author

Correspondence to Vesna Boraska Perica.

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The authors declare no competing interests.

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Kaličanin, D., Brčić, L., Ljubetić, K. et al. Differences in food consumption between patients with Hashimoto's thyroiditis and healthy individuals. Sci Rep 10, 10670 (2020). https://doi.org/10.1038/s41598-020-67719-7
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# data[].attributes.attachment_link.title
Differences in food consumption between patients with Hashimoto's thyroiditis and healthy individuals - Scientific Reports

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Food is considered as important environmental factor that plays a role in development of Hashimoto's thyroiditis (HT). The goal of our study was to identify food groups, assessed by food frequency questionnaire, that differ in consumption frequency between 491 patients with HT and 433 controls.

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Thyroid function and lipid profile in bipolar patients

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Thyroid function and lipid profile in bipolar patients

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Tamunoerenomie Inimgba
The purpose of the article was to determine the  prevalence of hypothyroidism in patients with bipolar disorder in comparison with the overall population. Based on previous research done in animal studies, there was considerable data that showed a relation between thyroid hormones and the neurotransmitter systems that play a role in mood disorders. A key finding in the study was that hypothyroidism was frequent in bipolar patients and patients had higher TSH values than controls. There was a significant association with obesity and disturbances in lipid profiles in these patients. Also there was a significant association with patients on lithium and valproic acid treatment. This relates to nutritional sciences because bipolar patients will require specific acre and nutritional diet when taking these specific drugs inorder to control their regulate their thyroid system, lipid profiles and weight. The clinical implications of the study was to identify the possible correlation of thyroid dysfunction in bipolar patients.
Ezzaher, Haj Mouhamed, D., Mechri, A., Neffati, F., Douki, W., Gaha, L., & Najjar, M. F. (2011). Thyroid function and lipid profile in bipolar I patients. Asian Journal of Psychiatry, 4(2), 139–143. https://doi.org/10.1016/j.ajp.2011.02.002

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More hypothyroidism and less hyperthyroidism with sufficient iodine nutrition compared to mild iodine deficiency—A comparative population-based study of older people

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More hypothyroidism and less hyperthyroidism with sufficient iodine nutrition compared to mild iodine deficiency—A comparative population-based study of older people

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The selected article that I chose for this module addressed the occurrence of thyroid diseases in a geriatric population with long standing recommended iodine intake of natural origin compared to mild iodine deficiency. I found this study to be important and related to this weeks module specifically because this article addressed the nutritional aspects that related to thyroid diseases and how a nutritional factor such as intake of iodine can affect the thyroid. The article addressed that both high and low intake of iodine are associated with occurrence of diseases. Intake of iodine is mainly found in the drinking water and the diet. The key finding to this study would be that a geriatric population who lived in an area with the recommended iodine intake supplied to every resident by a stable, natural source was found that fewer individuals exhibited thyroid dysfunction. I would say that the clinical implications of this study would be that if a patient or individual were to be presenting with thyroid issues, the levels of iodine intake should come into question. If the levels of iodine intake were found to be abnormal, they should be adjusted, hopefully helping the issues with the thyroid.

Andersen, Stig et al. “More Hypothyroidism and Less Hyperthyroidism with Sufficient Iodine Nutrition Compared to Mild Iodine deficiency—A Comparative Population-Based Study of Older People.” Maturitas 64.2 (2009): 126–131. Web.

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The Influence of Reducing Diets on Changes in Thyroid Parameters in Women Suffering from Obesity and Hashimoto's Disease

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The Influence of Reducing Diets on Changes in Thyroid Parameters in Women Suffering from Obesity and Hashimoto's Disease

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Ostrowska L, Gier D, Zyśk B. The Influence of Reducing Diets on Changes in Thyroid Parameters in Women Suffering from Obesity and Hashimoto's Disease. Nutrients. 2021 Mar 5;13(3):862. doi: 10.3390/nu13030862. PMID: 33808030; PMCID: PMC8000220.

This study is important because it links issues with the thyroid to obesity. Obesity is a very common issue today and it is interesting to apply it to a topic discussed in class. This study is also important because the subjects were pregnant women who suffer from thyroid disease. The aim was to reduce overall body fat and assess how that influenced their symptoms of thyroid disease. The study was conducting by reducing the daily caloric intake of the women while also using an elimination diet and then comparing the results to a control group that reduced their calories but did not participate in the elimination aspect. The results showed that the women who eliminated processed foods and sugars showed a significant difference compared to the control group. This study was done to show that controlling obesity would limit symptoms of thyroid disease and it was successful. However, it also shows that anyone can benefit from eliminating unhealthy foods from their diets.

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Breast and soy-formula feedings in early infancy and the prevalence of autoimmune thyroid disease in children.

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Breast and soy-formula feedings in early infancy and the prevalence of autoimmune thyroid disease in children.

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I chose this study because I felt it was important to be aware if feeding a baby with soy-formula or breast milk form the mother could be one of the causes of autoimmune thyroid disease in children. This is very important to know becaue autoimmune thyroid disease is one of the most prevalent autoimmune diseases in children. This study looked at 59 children with autoimmune thyroid disorder, 76 children who were siblings with those with the disorder and a control group. An important finding of this study was that most of the children who had the thyroid disorder were fed with soy-formula at an early age. This relates to nutritional sciences as this soy-formula does not contain the nutrients needed which is iodine to be able to help in the formation of thyroxine especially in infants. Thyroxine is important for many bodily functions to occur. The clinical implications of this study is physicians should encourage breast feeding mothers to use breast milk they produce or find alternative formulas that do not include soy in them to be able to prevent the high rise of autoimmune thyroid disease in infants.

Fort, P., Moses, N., Fasano, M., Goldberg, T., & Lifshitz, F. (1990). Breast and soy-formula feedings in early infancy and the prevalence of autoimmune thyroid disease in children. Journal of the American College of Nutrition, 9(2), 164–167. https://doi.org/10.1080/07315724.1990.10720366.

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Iodine status of consumers of milk-alternative drinks v. cows’ milk

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Iodine status of consumers of milk-alternative drinks v. cows’ milk

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I chose this study to make everyone aware that when choosing alternative products that they may be missing important nutrients found in the original food.  This study looked at a group of 2845 people in the UK where milk if the primary source of iodine.  When the data was collected (2014-2017), few milk alternatives were fortified with iodine and other essential vitamins and minerals.  The participants that solely drank milk alternatives were significantly more likely to suffer from iodine deficiency compared to those who drank cows milk either exclusively or in combination with milk alternatives.  As we have learned in this section, iodine is essential for thyroid function.  Today, iodine fortification is more common, but it is not necessarily done in all alternative milk products.  When choosing alternate foods, it is important to determine which nutrients may not be in the new source as opposed to the other and to add additional foods or supplements to compensate and prevent deficiencies.

Dineva, Rayman, M. P., & Bath, S. C. (2021). Iodine status of consumers of milk-alternative drinks v. cows’ milk: data from the UK National Diet and Nutrition Survey. British Journal of Nutrition, 126(1), 28–36. https://doi.org/10.1017/S0007114520003876

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Iodine status of consumers of milk-alternative drinks v. cows' milk: data from the UK National Diet and Nutrition Survey | British Journal of Nutrition | Cambridge Core

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We used data from the UK NDNS Rolling Programme (RP) database from years 7 to 9 (i.e. in the period between 2014/2015 and 2016/2017). The NDNS methodology has been described in detail elsewhere .

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Effects of levothyroxine treatment on pregnancy outcomes in pregnant women with autoimmune thyroid disease. Sidney Harm

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Effects of levothyroxine treatment on pregnancy outcomes in pregnant women with autoimmune thyroid disease. Sidney Harm

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Thyroid autoimmune disorder has been connected to higher rates of pregnancy complications such as placenta abruption, miscarriage, gestational hypertension and diabetes, as well as preeclampsia.1  Hyper and hypothyroidism is common within women of childbearing age which is why this subject is valuable in being studied further. This study looked further into a popular treatment for autoimmune thyroid disorders  and the impact on pregnancies. The therapy that was looked at more specifically in the study was Levothyroxine. The results of the study showed that individuals who had this therapy treatment did have a decreased prevalence of preterm delivery or other negative pregnancy outcomes. Nutritional recommendations for hyper and hypothyroidism is weight maintenance, and supplementation of vitamins D and B12 if the individual has low levels. It is important to note that the tested treatment therapy didn’t have a high prevalence of  negative pregnancy outcomes. In pregnancy nutritional needs for certain vitamins & micronutrients are increased due to needs of the fetus as well, in next studies there should be nutritional or supplemental trials to see the impacts on autoimmune thyroid  disorders in pregnant women.

References:

1.     Nazarpour, S., Ramezani Tehrani, F., Simbar, M., Tohidi, M., Alavi Majd, H., & Azizi, F. (2017). Effects of levothyroxine treatment on pregnancy outcomes in pregnant women with autoimmune thyroid disease. European journal of endocrinology, 176(2), 253–265. https://doi.org/10.1530/EJE-16-0548

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Maternal thyroid function in different conditions of iodine nutrition in pregnant women exposed to mild-moderate iodine deficiency: an observational study

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Maternal thyroid function in different conditions of iodine nutrition in pregnant women exposed to mild-moderate iodine deficiency: an observational study

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The focused article addresses if iodine supplemental products will benefit pregnant women. It’s important to know this information because if one is considering conception they should be aware of this possibility. Pregnant women are usually iodine deficient without taking some type of supplement due to the fetus. In order to maintain regulated level that has to be done so there isn’t a risk for high risk pregnancy, hypothyroidism, or congenital anomalies of the fetus. A key finding was that there was no significant increase in iodine levels when taking daily supplements in addition to using iodized salt. They found that taking iodine at a high rate in the early stages of pregnancy do more harm than good and can lead to maternal hyperthyrotrophinaemia. This is great information for clinical implications because if one is considering conception physicians can request a moderately to completely deficient woman to consume iodine months before pregnancy. Therefore, it will minimize thyroid deficiencies to an already susceptible immune system while pregnant.

Moleti, Di Bella, B., Giorgianni, G., Mancuso, A., De Vivo, A., Alibrandi, A., Trimarchi, F., & Vermiglio, F. (2011). Maternal thyroid function in different conditions of iodine nutrition in pregnant women exposed to mild-moderate iodine deficiency: an observational study. Clinical Endocrinology (Oxford), 74(6), 762–768. https://doi.org/10.1111/j.1365-2265.2011.04007.x

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Seonwook Kim: Prevalence of hyperthyroidism according to type of vegetarian diet

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Seonwook Kim: Prevalence of hyperthyroidism according to type of vegetarian diet

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My selected article studied hyperthyroidism and vegetarian diet. As we learned during the module 1, vegetarian diets may be associated with low prevalence of autoimmune disease. And Graves’ disease is an autoimmune disorder and is the most common cause of hyperthyroidism. This study investigated the prevalence of hyperthyroidism in a population of vegetarians.

The key finding of this study is that vegetarians carried lower odds of hyperthyroidism. The result indicates that vegan, lacto-ovo and pesco vegetarian diets were associated with lower risk compared with omnivorous diets. And this study is directly related to nutritional sciences. We know that vegetarian diets have been linked to lower body weight and BMI. Also, vegetarian diets contained high amounts of antioxidants, possible protective factors against autoimmune disease. The conclusion is that vegan and other vegetarian diets were associated with protection against prevalent hyperthyroidism.

This study may help to plan a diet for Graves’ disease patients clinically. Graves’ disease patients should be monitored for their weight and food to prevent malnutrition. And following vegetarian diets may be planned with drug administration for synergetic effects.

Tonstad S, Nathan E, Oda K, Fraser GE. Prevalence of hyperthyroidism according to type of vegetarian diet. Public Health Nutr. 2015 Jun;18(8):1482-7. doi: 10.1017/S1368980014002183. Epub 2014 Sep 29. PMID: 25263477; PMCID: PMC4377303.

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Prevalence of hyperthyroidism according to type of vegetarian diet

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Vegetarian diets may be associated with low prevalence of autoimmune disease, as observed in rural sub-Saharan Africans. Graves’ disease, an autoimmune disorder, is the most common cause of hyperthyroidism. We studied prevalence of hyperthyroidism ...

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The importance of nutritional factors and dietary management of Hashimoto’s thyroiditis - Esraa Zamzami

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The importance of nutritional factors and dietary management of Hashimoto’s thyroiditis - Esraa Zamzami

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For this week’s weekly wall, the paper I chose discusses the most important dietary management tips that play a critical role in Hashimoto’s thyroiditis. Many nutritional factors were thoroughly discussed, all of which significantly affect the disease pathology. However, I wanted to point out the importance of total energy and protein intake that this paper discussed. Many patients with Hashimoto’s thyroiditis suffer from overweight and obesity due to a reduction in their metabolism; however, many of these patients consume less energy than expected. For this reason, energy needs must be calculated individually, and encouraging patients to increase their physical activity is far more important than energy restricted diets. For protein, low protein intake was related to increases in the severity of thyroid damage, iodine deficiency, and elevated levels of TSH. Also, increasing the consumption of protein will help in weight reduction. The clinical implication of this study is that patients must meet their nutritional needs by consuming healthy, nutritious meals to avoid further complications.

Ihnatowicz, P., Drywień, M., Wątor, P., & Wojsiat, J. (2020). The importance of nutritional factors and dietary management of Hashimoto's thyroiditis. Annals of agricultural and environmental medicine : AAEM, 27(2), 184–193. https://doi.org/10.26444/aaem/112331

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Mitchell Watts: Influence of Dietary Habits on Oxidative Stress Markers in Hashimoto's Thyroiditis

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Mitchell Watts: Influence of Dietary Habits on Oxidative Stress Markers in Hashimoto's Thyroiditis

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This observational study compared the dietary habits of subjects with Hashimoto’s thyroiditis (HT) with normal thyroid gland function (euthyroid) compared with healthy controls, and the relationship with redox balance. In the study, patients with euthyroid HT reported significantly higher intake of animal foods (specifically red and processed meat), fats, and refined sugar; while the healthy control group reported higher intake of plant foods (vegetables, fruits, legumes, and nuts). There were no significant differences between the two groups on intake of cereals, whole grains, olive oil, and alcohol. Overall, the diets of HT subjects mimicked a typical western-type diet compared to a Mediterranean diet with the control group. To note, the Mediterranean diet consists of high intake of fiber, antioxidants, and vitamins, which have anti-inflammatory and antioxidant effects. Additionally, in HT subjects the activity of glutathione peroxidase and thioredoxin reductase and total plasma antioxidant activity were lower, and markers of oxidative stress were higher. Interestingly, the authors also refer to data from the Adventist Health Study-2, where a reduced risk of hyperthyroidism was noted in those consuming a vegan diet when compared with omnivores, while lacto-ovo and pescetarian diets were associated with intermediate protection.

This study is important and clinically relevant, because it suggests that reducing intake of animal proteins and fats and increasing intake of plant foods has a potentially protective effect on thyroid autoimmunity due to its positive influence on redox balance. This lifestyle change could reduce the risk for autoimmune thyroid disorders. As a side note, this type of diet differs from the Autoimmune Protocol diet, which has become popular in recent years. This is a modified paleo diet; it differs from the Mediterranean diet in that it avoids grains, legumes, nightshade vegetables, eggs, dairy, nuts and seeds, and alcohol. However, the research on the AIP diet is limited, it would be very restrictive and potentially hard to follow, and may lead to certain nutrient deficiencies.

Ruggeri, R. M., Giovinazzo, S., Barbalace, M. C., Cristani, M., Alibrandi, A., Vicchio, T. M., Giuffrida, G., Aguennouz, M. H., Malaguti, M., Angeloni, C., Trimarchi, F., Hrelia, S., Campennì, A., & Cannavò, S. (2021). Influence of Dietary Habits on Oxidative Stress Markers in Hashimoto's Thyroiditis. Thyroid : official journal of the American Thyroid Association, 31(1), 96–105. https://doi.org/10.1089/thy.2020.0299

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Influence of Dietary Habits on Oxidative Stress Markers in Hashimoto’s Thyroiditis - PubMed

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Background: There is a growing awareness that nutritional habits may influence risk of several inflammatory and immune-mediated disorders, including autoimmune diseases, through various mechanisms. The aim of the present study was to investigate dietary habits and their relations…

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Richard Adefioye:     Influence of Short-Term Dietary and Therapeutic Iodine Restriction on the Therapeutic Effects of Radioactive Iodine Therapy in Patients with Graves’ Disease

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Richard Adefioye:     Influence of Short-Term Dietary and Therapeutic Iodine Restriction on the Therapeutic Effects of Radioactive Iodine Therapy in Patients with Graves’ Disease

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I came across this paper and I just found it interesting since radioactive iodine was mentioned in the lecture as one of the means of diagnosing Grave's disease. But beyond this,  radioactive iodine is also used as a treatment for Graves’ disease, as it promotes the destruction of thyroid epithelial cells when the inorganic iodine radioisotope is absorbed.

But for this study, the authors investigated whether or not the therapeutic effects of  radioactive iodine treatment (RAIT) was affected by dietary or other sources of therapeutic iodine taken by the patients before starting RAIT.

The key finding of this study was that there was no significant difference whether or not the patients consumed iodine from other sources up to the start of their RAIT regimen.

I personally think this is important for patients with grave's disease because it's one less thing to worry about regarding their daily nutrition.

Nishio, R., T. Uchida, L. Suzuki, H. Onose, H. Goto, E. Yamada, H. Satoh, and H. Watada. 2020. Influence of Short-Term Dietary and Therapeutic Iodine Restriction on the Therapeutic Effects of Radioactive Iodine Therapy in Patients with Graves' Disease. Thyroid 31(3):439-445. doi: 10.1089/thy.2020.0126

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Paulina Ihnatowicz, Paweł Wątor, Małgorzata Ewa Drywień. Supplementation in Autoimmune Thyroid Hashimoto’s Disease. Vitamin D and Selenium. Journal of Food and Nutrition Research. Vol. 7, No. 8, 2019, pp 584-591. http://pubs.sciepub.com/jfnr/7/8/6

This is a review of a combination of studies done on supplementation in autoimmune thyroid Hashimoto's Disease (HT) with Vitamin D (VD) , Selenium (Se), and possibly Magnesium (Mg). The overarching goal was to try to shed light on how vitamin D status affects HT, how selenium status affects HT, and the possibility of combining the two to see how they affect each other and the disease course by reviewing multiple clinical studies that have included these nutrients as a therapy for HT. Honestly I thought it was important because I have low Vitamin D and a family history of thyroid disease and I wanted to see the effects that vitamin D has on the thyroid. What I found was that there are actually a lot of people with low vitamin D and most of the people with HT actually do have low vitamin D serum concentrations so supplementation could be an important avenue for mitigation of disease.

Although this review reports conflicting results from different studies and mentions the needs for more clinical longitudinal studies, there was an interesting study that administered concomitant use of cholecalciferol (inactive form of vitamin D) along with selenomethionine (organic Se compound) in young women with HT. Divided into 2 groups, both were given 4000 IU of VD daily, but one group was given 200microg of Se daily and one was not. The VD serum levels were a mean 20-21 ng/mL for both groups, but after the study the Se-treated groups VD serum levels were 43.2 compared to 41.1 ng/mL in the nonSe-treated group. TPO-Abs and TG-Abs decreased 38.5% and 33.8%, respectively, for the Se-treated group. For the VD only nonSe-treated group TPO-Abs and TG-Abs decreased 21.5% and 22.6%, respectively at the end of the study period. This indicated that Se and VD treatment has better effects on the circulating thyroid antibodies and that Se potentiates the effects of VD. This would mean that in addition to adding more vitamin D dense foods to the diet of someone with HT, adding more Se foods (example Brazil nuts) concomitantly to the diet would help the effectiveness of the VD and could decrease the effects of HT.

Clinically, it sheds light on the importance of vitamin D in immune function and therefore autoimmune diseases, but also the importance of drug-drug interactions for different nutrients and how one nutrient can bolster the effects of the other. The study does have limitations, like the fact that Se serum level was not measured at the start, but I think it's an intriguing start to find ways of mitigating HT effects. For example, if your patient is resistant to VD treatment alone, adding Se supplementation could help make the VD treatment more effective. Interestingly, as with iodine, Se has a U-shaped relationship between concentration and disease, too little Se has negative effects, but too much also has negative effects. Combining VD, with Se, Mg, or levothyroxine for HT patients might alleviate disease symptoms better than levothyroxine or VD alone & is something to think about for your patient.

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Katelyn Spain: Smoking status and changes in thyroid-stimulating hormone and free thyroxine levels during a decade of follow-up: The Tehran thyroid study

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Katelyn Spain: Smoking status and changes in thyroid-stimulating hormone and free thyroxine levels during a decade of follow-up: The Tehran thyroid study

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The purpose of this study was to identify the correlation of smoking and the alterations of thyroid hormones overtime. This study is important because it shows that TSH is decreased and FT4 is increased in people that smoke. Lowered TSH levels in the thyroid are an indication of hyperthyroidism. Increased FT4 levels are an indication of hyperthyroidism, as well. Hyperthyroidism is what contributes to autoimmune diseases, such as Graves disease. A significant finding of this study was that of the three different groups (non-smokers, ex-smokers, and smokers) the non-smoking group and ex-smoking group exhibited a statistically significant increase in TSH levels during the follow-up period, while the smokers had decreasing TSH levels. This shows that smoking is contributing to the decrease in TSH in the body and is poorly affected overall nutrition of the body. The clinical implications of this study are that in the effort to prevent and treat patients that exhibit hyperthyroidism and smoke, that they need to be aware of smoking and its potential cause of hyperthyroidism and levels of hormones in the body.
Kadkhodazadeh, H., Amouzegar, A., Mehran, L., Gharibzadeh, S., Azizi, F., & Tohidi, M. (2020). Smoking status and changes in thyroid-stimulating hormone and free thyroxine levels during a decade of follow-up: The Tehran thyroid study. Caspian journal of internal medicine, 11(1), 47–52. https://doi.org/10.22088/cjim.11.1.47

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Abstract

Background:

Smoking can cause thyroid disorders; the aim of the present study was to investigate the association between smoking status and changes in thyroid hormone levels among adult males during a decade long follow-up of in the Tehran Thyroid Study (TTS).

Methods:

Data of 895 adult males (smokers=115, non-smokers=691, ex-smokers=89) participants of the TTS without any previously known thyroid disease were analyzed. To examine trends of changes in thyroid hormone levels in these three groups, generalized estimating equation models were used. The interaction between the smoking status and each phase of the study was checked in a separate model.

Results:

Age and BMI adjusted trends of free thyroxine (FT4) demonstrated a non-significant decrease in participants (P=0.121) and thyroid-stimulating hormone (TSH) gained a significant average increase value over time in the total population (adjusted marginal mean of TSH=1.15 mU/L in phase 1, vs. 1.75 mU/L in phase 4, P<0.0001). Of the three groups, non-smokers and ex-smokers showed statistically significant increases in TSH during the follow-up period, whereas the smoker group had lower increases in TSH levels, changes from phase 1 until phase 2 among smokers were 38.46%, vs 43.54% and 52.94% in the ex and non-smokers, respectively.

Conclusion:

TSH was lower and FT4 was higher in smokers compared with the other smoker groups, although TSH level shows no decreasing trend over time in this group. The increasing trend of TSH in smokers was similar to ex and non-smokers. No difference was seen in FT4 trends among the smoking groups.

Key Words: Hypothyroidism, Hormones, Thyroid, Smoking

Scientific evidence shows that smoking is the most important and preventable risk factor for health problems and mortality ( 1). According to a WHO report, the total number of smokers is increasing in the whole world ( 2). Tobacco smoke contains about 4800 substances, including at least 200 toxicant and 80 known or suspected carcinogens ( 3). Effects of smoking on thyroid disorders have caused major concern, some studies demonstrated that smoking did not have any significant relationship with thyroid functions ( 4), while others reported that smoking is associated with a decreased level of anti‐thyroid peroxidase antibodies (anti‐TPO Ab) and thyroid‐stimulating hormone (TSH) levels ( 5- 7).TSH and free thyroxine (F4) levels are important indicators used to diagnose thyroid disorders ( 8) and assessing thyroid function according to smoking status. A population-based study showed lower mean of TSH values in smokers compared with non or former smokers ( 9).

Another study conducted in a Korean population reported mean serum TSH level in current smokers was significantly lower than that in non-smokers ( 10). Jorde et al. also revealed that TSH level (adjusted for age, sex) and BMI was lower in smokers compared to nonsmokers ( 11).

Objectives: Although many studies have been conducted about the relationship between smoking and thyroid disorders, especially TSH, most theses are cross-sectional studies and few studies have assessed the changes of thyroid hormone levels in smoker populations over time in a cohort study. Considering the limited available data, the aim of the present study was to investigate the association between smoking status and changes in thyroid hormone levels among adult males during a decade long follow-up in the Tehran thyroid study (TTS).

Methods

Study population: Detailed descriptions of TTS have been published elsewhere ( 12, 13)briefly, the TTS, a population-based cohort study performed on a representative sample of residents of district No.13 of Tehran (the capital city of Iran), was designed to evaluate the prevalence and incidence of thyroid diseases and related risk factors in adult population. TTS has two major components: a cross-sectional study (1999-2001) and a prospective follow-up study at intervals of approximately 3 years.

In the current study, from a total 4174 participants with aged ≥20 years, we excluded women for low prevalence of smoking (n=1968), those using any medications related to thyroid disorders (n=786), those with any thyroid dysfunction or thyroid surgery history or cancer (n=786) and participants who had no follow up or missing data (n=321). Eventually 895 subjects with complete data, from 1999 until March 2012 were enrolled in the present study (). The median follow-up duration was 9.57±0.87 years. The study design was approved by the Institutional Review Board (IRB) of the Research Institute for Endocrine Sciences (RIES), Shahid Beheshti University of Medical Sciences.

Clinical and laboratory measurements: All participants, after signing informed written consent forms were invited to participate in the TTS. Baseline and follow up information including age, smoking status, medication use and thyroid disorders history were collected by trained interviewers, using a standard questionnaire. Details of anthropometric measures obtained using standard protocols, including weight and height have been reported elsewhere ( 14). Body mass index (BMI) was calculated by dividing weight (kg) by square of height (m ²). A venous blood sample was drawn between 7:00 and 9:00 AM after 12-14 hours of overnight fasting for each participant. Free thyroxine (FT4) and thyroid stimulating hormone (TSH) were measured on −70°C stored serum samples by electrochemiluminescence immunoassay using Roche Diagnostics kits & Roche/ Hitachi Cobas e-411 analyzer (GmbH, Mannheim, Germany). The sensitivity of TSH and FT4 measurements were 0.005 μIU/ml and 0.30 pmol/l, respectively. Lyophilized quality control material (Lyphochek Immunoassay plus Control, Bio-Rad Laboratories) was used for accuracy assessment of hormonal assays; intro- and inter-assay coefficients of variation for TSH were 1.4% and 4.6% and for FT4 assay were 1.3 % and 3.3 %, respectively. Details of laboratory assessments have been reported elsewhere ( 14).

Definition of terms: Current smokers were defined as participants who were smoking cigarettes daily or occasionally, as well as those who used water pipe or pipe at the time of the study. Ex-smokers were defined as participants who used to smoke in the past. All participants who had never smoked were called non-smokers.

Statistical analysis: Baseline characteristics of participants are reported as mean±standard deviation (SD) for continuous variables. TSH is reported as median and inter-quartile range (IQR); categorical variables are given as a number (percent). Normality assumption was checked using the Shapiro- Wilk test. One-way ANOVA test (Kruskal-Wallis H test) was used to explore differences in descriptive baseline characteristics between the smoker, non-smoker and ex-smoker groups.

To analyze the effect of smoking status on the trend of TFT, we used generalized estimating equations (GEE), a statistical method that facilitates the analysis of longitudinal data for many different distributions. We used an exchangeable correlation structure with a random intercept for this study. At first step, models were developed at two hierarchical levels; age-adjusted (adjusting for age and phase) and multivariate-adjusted (adjusting for age, examination phase, BMI, and smoking status) in the total population. In the second step, we developed the models in three groups, separately. Again, models were developed at two hierarchical levels; age-adjusted (adjusting for age and phase) and multivariate-adjusted (adjusting for age, examination phase, and BMI). P<0.05 were considered significant. All analyses were performed using STATA statistical software (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP)

Results

Overall, 895 men participants, with a mean age of 41.67 (SD=14.15) years were included in the analysis; of these, 115 (12.85%) cases were current smokers, 89 (9.94%) were ex-smokers, and approximately 691(77.21%) of them had never smoked previously. As shown in , no significant difference was observed in mean BMI among the three groups. Mean TSH among the non-smoker, ex-smoker and smoker groups were 1.35, 1.35 and 0.97, respectively (P=0.01), similar to the means for FT4 was 1.23, 1.24 and 1.27 respectively (P=0.047).

Table 1

We observed a significant decrease in FT4 levels during the study; however, that trend did not remain significant after adjusting for BMI and smoking status (P=0.12, ). TSH levels significantly increased during the study in the total population of both models. (p<0.01, ).

Table 2

shows the results of GEE for the three groups. TSH increased significantly over a decade in three smokers (mean TSH= 0.93 and 1.26 in visit 1 vs. visit 4), ex-smoker (mean TSH= 1.24 and 1.78 in visit 1 vs. visit 4) and non-smoker group (mean TSH=1.19 and 1.82 in visit 1 vs. visit 4). We observed a statistically significant decrease in FT4 levels during the study only in non- smokers (p<0.01).

Table 3

Discussion

To the best of our knowledge, the present study is the first study conducted within large cohort study in the Middle East region reporting the trend of thyroid hormones based on their smoking status among adult men. Results showed that FT4 levels remained more stable in individuals with different smoking status, compared to TSH, which showed dramatic increases in all three groups. Smokers however, generally experienced lower rates of change in their TSH, compared to the other groups. Results consistent with findings of other studies demonstrating that smoking is associated with lower TSH concentrations.

Regarding cross-sectional analysis, we found that smokers had lower serum TSH levels than the two groups. Previous studies show similar results, i.e. smoking is associated with lower serum TSH level ( 9, 10, 15). One study conducted in an iodide replete-area showed that smoking reduced the risk of subclinical hypothyroidism in people with high iodine intake. Results of this study suggest that iodine intake is an important variable to elucidate associations between smoking and TSH( 15). Although, we observed a significant increasing trend in TSH among the three smoking groups, the mean percentage change in TSH levels between these three groups differs. Previous studies show that, in former smokers, TSH increases with time after smoking cessation; it is only 18 years in men and 5 - 10 years in women that these groups achieve the never smoker status ( 16- 18). However our study shows different results, the magnitude of the increased mean value of TSH in the smoking group was lower than the ex and non-smoker groups after 10 years (38.46 vs 43.54 and 39.56 respectively), Findings not in agreement with others groups. These results suggest that TSH level did not show decrease over time in the smoker group and trend of increasing in TSH level is similar to that of non-smoker population. It is difficult to compare the results of the present study with data of other epidemiologic studies on smoking and thyroid abnormalities as different methods are used for different aims. These cross-sectional findings provided some insight on the lower levels of TSH among smokers vs non-smokers, further follow up studies are needed to determine and confirm trends of TSH changes in this group.

The result of the present study revealed that mean serum FT4 concentrations in smokers are lower than non-smokers, findings in line with thyroid hormone changes within normal pituitary feedback; however, FT4 trend did not differ over 10 years. Data show conflicting results regarding the associations between FT4 concentrations and smoking; some studies reveal lower FT4 levels among smokers vs nonsmokers ( 16, 19). Findings contrary to those of two Korean studies showing that FT4 concentrations did not differ based on smoking status ( 7, 15). The present study has several limitations, we classified smoking status based on self-reports and the possibility of misclassification cannot be neglected. Another limitation is that we have not considered different categories of smoking for establishing the dose-response effect of smoking status. As for the strengths of the present study, we have used the data of an ongoing cohort study with a relatively long period of follow-up to assess the trends of thyroid hormones overtime.

In conclusion, the results show that although mean TSH values among smokers are much lower than non-smokers and ex-smokers at baseline (cross-sectional comparison), the 10-year-trend showed a 38.46 increase from baseline values. Results suggest the TSH level showed no decreasing trend over time among smokers. For TSH the increasing trend in smokers was similar to those of ex and non-smokers, despite previous insight on lower TSH values in smokers, although the increasing trend was lower in smokers. FT4 was higher in smokers at baseline but showed no difference between the smoking groups. Furthermore, follow-up studies are needed to determine trends of TSH change in this group.

Acknowledgments

The authors wish to acknowledge Ms. Niloofar Shiva for the critical editing of English grammar and syntax of the manuscript.

Funding:

This study is a part of a thesis approved by Shahid Beheshti University of Medical Sciences. For this thesis, we used data from cohort study, Tehran thyroid study (TTS). For which the support of Research Institute for Endocrine Sciences (RIES) is sincerely appreciated.

Conflict of Interest:

The authors declare that they have no conflict of interest.

Ethical approval:

All procedures performed in TTS study were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and informed consent was obtained from all individual participants included in the study.

References

14. Azizi F, Ghanbarian A, Momenan AA, et al. Prevention of non-communicable disease in a population in nutrition transition: Tehran Lipid and Glucose Study phase II. [[ PMC free article] [ PubMed] Google Scholar]

16. Soldin OP, Goughenour BE, Gilbert SZ, Landy HJ, Soldin SJ. Thyroid hormone levels associated with active and passive cigarette smoking. [[ PMC free article] [ PubMed] Google Scholar]

18. Benedict MD, Missmer SA, Ferguson KK, et al. Secondhand tobacco smoke exposure is associated with prolactin but not thyroid stimulating hormone among nonsmoking women seeking in vitro fertilization. Environ Toxicol Pharmacol. 2012;34:761-7. [[ PMC free article] [ PubMed] Google Scholar]

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Smoking status and changes in thyroid-stimulating hormone and free thyroxine levels during a decade of follow-up: The Tehran thyroid study

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Smoking can cause thyroid disorders; the aim of the present study was to investigate the association between smoking status and changes in thyroid hormone levels among adult males during a decade long follow-up of in the Tehran Thyroid Study (TTS). Data of 895 adult males (smokers=115, non-smokers=691, ex-smokers=89) participants of the TTS without any previously known thyroid disease were analyzed.

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The research paper selected for this week is titled: “Detection of Alterations in the Gut Microbiota and Intestinal Permeability in Patients with Hashimoto Thyroiditis.”

This research paper is a 2021 cohort study from São Paulo State University (UNESP), São Paulo, Brazil.  They have evaluated alterations in the gut microbiota in Brazilian patients with Hashimoto Thyroiditis (HT) and correlated this data with dietary habits, clinical data, and systemic cytokines and zonulin concentrations.

This study is important because HT is thought to be the most common autoimmune disease with worldwide prevalence of 10-12%.   The study evaluated stool samples from 40 patients with HT and 53 controls, they were analyzed to evaluate difference in the bacterial type and quantity.  The serum cytokine levels were compared between HT patients and controls.  Zonulin (a gut protein associated with Tight junctions and leaky gut) concentrations were compared.  HT patients and controls dietary habits were recorded by a food frequency questionnaire and compared.

The key findings from this study are that the zonulin serum concentrations were significantly increased in patients with HT when compared with controls, implying a leaky gut.  High zonulin serum concentrations correlated with elevated interferon-gamma- and inversely correlated with Interleukin-2 (regulators of the immune system.)  A significant increase in the Bacteroides species was observed in the samples derived from patients compared with control subjects. A significant decrease in the Bifidobacterium species was observed in the stool samples isolated from patients with HT when compared with controls. The authors also found an inverse correlation between animal-derived protein consumption by patients and the quantities of Bacteroides species

Clinical implication from of this study are not directly obvious, but is directional in our efforts to prevent and treat HT.  Will scientist discover ways to promote an healthy microbiome and ways to prevent leaky gut with subsequent decrease incidence of HT?   Just as we use a lipid profile today, in the future will we be checking our microbiome and zonulin concentrations to make corrections?1

Cayres LCF, de Salis LVV, Rodrigues GSP, et al. Detection of Alterations in the Gut Microbiota and Intestinal Permeability in Patients with Hashimoto Thyroiditis. Front Immunol. 2021;12:579140. Published 2021 Mar 5. doi:10.3389/fimmu.2021.579140

Richard Proudfoot

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Thyroid Diseases and the Heart- Ashley Wahlman

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Thyroid Diseases and the Heart- Ashley Wahlman

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I found this to be a very interesting article discussing some of the most significant signs and symptoms for thyroid diseases which tend to be cardiac manifestations. As mentioned in the article they discussed how this is a symptom that is typically overlooked in clinical practice. Also, when patients present with pulmonary hypertension it is important to assess the thyroid function. One key finding in this study is that sinus tachycardia is the most common rhythm disturbance in patients with hyperthyroidism. A low serum TSH level is also low in patients with new onset atrial fibrillation. Testing the TSH level in patients with a sudden onset of atrial fibrillation is important for also diagnosing them with a thyroid disease. You can restore TSH levels with intaking more iodine, which would be located in more fish.  The clinical implications of this study is that we can be more aware of other clinical manifestations that may be a sign of a thyroid disorder that may appear first such as atrial fibrillation.

Klein, I., & Danzi, S. (2016). Thyroid Disease and the Heart. Current problems in cardiology, 41(2), 65–92. https://doi.org/10.1016/j.cpcardiol.2015.04.002

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Abstract

Thyroid hormones have an intimate relationship with cardiac function. Some of the most significant clinical signs and symptoms of thyroid disease are the cardiac manifestations. In both hypothyroidism and hyperthyroidism, the characteristic physiological effects of thyroid hormone can be understood from the actions at the molecular and cellular level. Here we explore topics from the metabolism and cellular effects of thyroid hormone to special considerations related to statin and amiodarone therapy for the alterations in thyroid hormone metabolism that accompany heart disease.

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anti-arrhythmia agents / adverse effects

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national center for biotechnology information

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Thyroid hormones have an intimate relationship with cardiac function. Some of the most significant clinical signs and symptoms of thyroid disease are the cardiac manifestations. In both hypothyroidism and hyperthyroidism, the characteristic physiological effects of thyroid hormone can be understood ...

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Iodine and Thyroid Hormones During Pregnancy

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Iodine and Thyroid Hormones During Pregnancy

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This week's article discusses how Iodine supplementation is important during pregnancy. This topic was chosen based on previous knowledge from a physiology course that discussed the relationship between thyroid disease and iodine. Iodine is an essential micronutrient that’s generally found in seafood. Many environmental and geographical factors influence the epidemiology of thyroid disorders, and even relatively small differences in the level of iodine intake within a population have profound effects on the occurrence of thyroid abnormalities. Iodine is required for the synthesis of thyroxine(T4) and triiodothyronine(T3), important thyroid hormones. Iodination of thyroglobulin occurs which transports T3 and T4 into the thyroid follicular cell where the complex is cleaved and free T3 and T4 enter the blood. T3 and T4 are important hormones in fetal neuron development. If the mother has low levels of iodine, low levels of T3 and T4 the fetus can cause impaired brain development which can lead to cretinism. Not only is iodine important for brain development but also is important because it can prevent hypothyroidism induced by pregnancy. Obstetrician’s should consider iodine supplements for patients that are pregnant or looking to become pregnant.

​​Pérez-López FR. Iodine and thyroid hormones during pregnancy and postpartum. Gynecol Endocrinol. 2007 Jul;23(7):414-28. doi: 10.1080/09513590701464092. PMID: 17701774.