Abstract
Context
Although, many studies have been made on the clinical course of autoimmune thyroiditis, this study focused on women and the factors effecting the natural course such as Selenium.
Objective
The study aimed to determine Hashimoto’s thyroiditis (HT) clinical course in adults and the factors that could affect it.
Design
The study was in a retrospective manner between 2010-2018.
Subjects and Methods
101 patients with HT were followed for 60.7±32.7 months. Biochemical and ultrasonographic data were collected. We investigated whether the age at diagnosis, family history, smoking habits, levothyroxine replacement therapy, and serum selenium (Se) levels influenced the disease course.
Results
No relationship was observed between age and thyroid functions, thyroid volumes (TV), and autoantibody (Ab) levels at diagnosis. Ab levels were irrelevant with TV, echogenicity, and nodularity at diagnosis. However, initial TSH levels were significantly associated with anti-TPO levels (p=0.028, r=0.218). In the untreated group, thyroid functions seemed to be stable. TV decreased significantly in both treated and untreated patients (p<0.001). The decrease in TV was significantly higher in the treatment group (p=0.002). In euthyroid and subclinical hypothyroid patients, levothyroxine therapy did not affect the decrease in TV. Ab levels remained stable in untreated patients, but anti-TPO levels significantly decreased in treated patients (p<0.001). Smoking seemed to increase only anti-Tg levels (p=0.009). Family history was not associated with any of the studied parameters. Serum Se level was negatively correlated only with thyroid echostructure and only in treated patients. TV showed a “Gaussian distribution” in all patients at the diagnosis and at the end, independent of levothyroxine treatment.
Conclusions
Most euthyroid patients remained euthyroid during five years of follow-up. The decrease in TV was significantly prominent with LT4 treatment. Importantly, TV followed a normal distribution instead of the bimodal distribution that is classically described.
Keywords: Autoimmune thyroiditis, thyroid autoantibodies, thyroid volume, Selenium
Introduction
Hashimoto’s Thyroiditis (HT) (chronic autoimmune thyroiditis) is the most common cause of primary hypothyroidism in iodine sufficient areas of the world. The prevalence of HT ranges between 5-15% in females and 1-5% in males (1).
Although progress to atrophic hypothyroidism resulting from autoimmune destruction of the thyroid gland has been anticipated in goitrous HT, it could not be proved by clinical studies (2). Most of the studies evaluating the natural course of HT cover the pediatric age group. Pediatric studies emphasized that not all the patients had developed hypothyroidism, and the patients with thyroid dysfunction might regain the thyroid functions after a 5-6 years of follow-up (3,4). The clinical course of HT may be miscellaneous. The only clinical trial, including morphological and functional follow-up in the adult population, was reported by Carlé et al. They found a normal distribution of thyroid volume in primary autoimmune hypothyroidism. Cases with thyroid atrophy or goiter are only extremes within this distribution and do not represent separate disorders. Levels of circulating antibodies were higher in higher thyroid volumes, and thyroid volume correlated negatively with echogenicity. Patients with the smallest volumes had more severe hypothyroidism biochemically at the time of diagnosis (5).
The effect of the thyroid hormone treatment on the disease course is controversial, especially in euthyroid patients. In the study of Padberg et al., L-Thyroxin (LT4) treatment given for one year decreased the autoantibody levels against thyroid peroxidase (anti-TPO) and the number of B lymphocytes in euthyroid patients but did not affect the thyroid volumes (TV) (6). In another study conducted in the pediatric age group, with levothyroxine (LT4) treatment, TV decreased in euthyroid and hypothyroid goitrous HT patients, whereas it decreased in hypothyroid and did not change in euthyroid non goitrous children (7).
The relationship between the thyroid functions, the thyroid autoantibodies, and the thyroid gland’s ultrasonographic appearance is also not demonstrated. Takamatsu et al. reported that anti-TPO positivity was correlated with decreased TV but not with thyroid hypoechogenicity. In contrast, anti-thyroglobulin (anti-Tg) positivity was correlated with the thyroid’s pseudonodular structure in ultrasonography, but not with TV, in an adult population. In this study, hypothyroidism was more prominent in anti-TPO positive patients (8).
On the other hand, recent studies presented a direct relationship between smoking and thyroid gland disorders. Smoking might increase TV as well as the nodularity of the gland (9,10). The effect of smoking on the course of HT is still a matter of debate.
Apart from the essential trace element iodine, Selenium (Se) is a co-factor for all three deiodinases that convert thyroxine into triiodothyronine in the form of selenocysteine and is required for appropriate thyroid hormone synthesis, activation, and metabolism. The selenoenzyme families of glutathione peroxidases (GPx) and thioredoxin reductases (TRx) possess powerful antioxidant properties and form a complex defense system that protects thyrocytes from oxidative damage; thus, serum Se levels can be correlated with the course of HT (11-13).
The objective of the current study is to determine the functional and morphological course of HT in adult females and examine the possible effects of the factors such as smoking, family history of autoimmune thyroid disease (AITD), autoantibody levels, LT4 treatment, and serum Se levels on the course of the disease.
Material AND Method
We evaluated the hospital’s database and recorded the laboratory, radiological, and demographic information of the female participants retrospectively. For the diagnosis of HT, at least two of the three criteria mentioned below were used i)At least one of the thyroid autoantibodies (antiTPO and/or anti-Tg) ≥ 100 IU/mL (0-60 IU/mL) ii)Typical ultrasonographic appearance of the thyroid gland (pseudonodular appearance, hypoechogenicity), iii)Cytology relevant to HT. The patients were screened for the history of AITD in their first degree relatives, smoking habits, LT4 treatment and evaluated with thyroid function tests, serum thyroid autoantibodies levels, serum Se levels, and standard thyroid ultrasonography performed at least two times, initially at the time of diagnosis and the end of the follow-up.
The study was in accordance with the ethical standards of the institutional research committee of Ankara University (Decision number I7-475-20) and with the Helsinki declaration,
LT4 treatment was given when Thyroid Stimulating Hormone (TSH) ≥ 10 mIU/L or to premenopausal women with TSH 5-10 mIU/L and high thyroid autoantibodies.
Thyroid Function Tests, Thyroid Autoantibodies, Se levels
Serum TSH, free thyroxine (fT4), free triiodothyronine (fT3) concentrations were determined by immunometric chemiluminescence (Elecsys 170®). Serum anti-TPO and anti-Tg concentrations were determined by competitive radioimmunoassay (Brahms® Dynotest). Serum Se levels were measured by atomic absorption spectrometer and FIAS 100 hydrid system (Perkin Elmer®).
Thyroid ultrasonography
Thyroid volumes were estimated using real-time sonography with a General Electric® Logiq 200 and Logiq 400 ultrasound machine, using a 7.5 MHz linear-array transducer by one of the two endocrinologists who are experienced in thyroid ultrasonography. Inter-observer variability between these two sonographers were less than 15%, proven by repeated testing on 50 patients. For determining thyroid size by ultrasonography, longitudinal and transverse scans were performed, allowing the measurements of the depth (d), the width (w), and length (l) of each lobe. The volume of the lobe was calculated by the formula: V (mL) = π/6 x d x w x l (cm) (14). The thyroid volume was the sum of the volumes of both lobes. The thyroid echogenicity was classified as i) diffuse homogeneous, ii)mild, iii)moderate, and iv)severe hypoechogenicity.
Statistical analysis
Pearson correlation test, Chi-square test, Student’s T-test, Mann-Whitney-U test, T-test in paired samples, and Wilcoxon test in paired samples were used in statistical analysis where appropriate. The direction and the strength of the relationship among continuous variables such as thyroid function tests (TSH, T4, T3), thyroid autoantibodies (anti-TPO, anti-Tg), serum Se levels, and TV and cigarette packages-year were studied with Pearson and Spearman’s coefficient. The difference in the change in TV between the patients treated with LT4 and the patients receiving no treatment was determined by covariance analysis after excluding anti-TPO and anti-Tg effects. We performed a statistical analysis using SPSS software version 15 (SPSS Inc., Chicago, IL, USA).
Results
The mean follow-up period was 60.7±32.7 months. There were 101 women whose mean age at diagnosis was 39.4±12.8 years. The percentage of the history of AITD in the first degree relatives was 43.6%. 32.7% of the group were smokers with a mean quantity of 14.1±13.2 package/year.
At the time of diagnosis, 34% of the patients were euthyroid (TSH: 0.3-4.5 mIU/L, fT4: 10-22 pmol/L, fT3: 3-6.5 pmol/L), 47% of the patients were subclinically hypothyroid (TSH>4.5 mIU/L, fT4: 10-22 pmol/L, fT3: 3-6.5 pmol/L), 16% of the patients were overt hypothyroid (TSH>4.5 mIU/L, fT4<10 pmol/L) and 3% of the patients were thyrotoxic (i.e., hashitoxicosis). The median anti-TPO level was 310.1 (4.4-9781) IU/mL, and the median anti-Tg level was 133.5 (2.2-9186) IU/mL. The mean TV was 16.2±10 mL.
During the observation period, 30.7% (n=31) of the patients did not receive any treatment, while 69.3% (n=70) of the patients received L-Thyroxin treatment. The mean treatment period was 60.9±34.3 months in the group, and the mean dose was 91.5±31.9 µg/day. The characteristics of the patients were given at diagnosis and at follow up in Table 1.
Table 1.
Median levels of thyroid autoantibodies (anti-TPO and anti-Tg), mean thyroid volumes and the thyroid status of the participants with or without levothyroxine replacement
| LT4 replacement (n=70) | Without LT4 replacement(n=31) | |||||
|---|---|---|---|---|---|---|
| At diagnosis | At the end of follow up (mean±… months) | p | At diagnosis | At the end of follow up (mean±… months) | p | |
| Thyroid status | ||||||
| Euthyroid | 10(14.5%) | 8(11.4%) | 24(77.4%) | 24(77.4%) | ||
| Subclinical | 43(62.3%) | 6(8.6%) | 4(12.9%) | 7(22.6%) | ||
| hypothyroid | ||||||
| Hypothyroid | 16(23.2%) | 1(1.4%) | - | - | ||
| Hashitoxicosis | - | - | 3(9.7%) | 0(0%) | ||
| AntiTPO(IU/mL)# | 432(6.9-9781) | 204(5-7873) | <0.001* | 167(4.4-5287) | 212(5.3-1463) | 0.445 |
| Anti-Tg (IU/mL)# | 142(2.2-9186) | 203(2.2-4000) | 0.274 | 128(10.3-2217) | 157.1(17.5-653.4) | 0.524 |
| Thyroid vol (mL)¶ | 14.5±9.2 | 9±5.5 | <0.001* | 20±11 | 17.8±10.7 | <0.001* |
*p<0.05 is statistically significant, # paired Wilcoxon test ¶paired student’s t test.
No relationship was observed between the age and thyroid function, TV, autoantibodies at the time of diagnosis. TSH level was negatively correlated with TV (p=0.002, r=-0.312) and positively correlated with anti-TPO levels (p=0.028, r=0.218) while there was no statistically significant relationship between TSH and anti-Tg (p=0.553) at diagnosis. There was no significant relationship between thyroid autoantibody levels and thyroid volume, parenchyma echogenicity, and nodularity at diagnosis. When patients were divided into functional subgroups such as euthyroid, subclinically hypothyroid, and overt hypothyroid, in subclinically hypothyroid patients, the anti-TPO level was found to be positively correlated with TV (p=0.007, r=0.39).
In patients who did not receive LT4, thyroid functions seemed to be stable during the observation period (60.9±34.3 months). Among the twenty-four euthyroid patients, twenty of them remained euthyroid, but four of them turned out to be subclinically hypothyroid. Among those four patients, three remained subclinically hypothyroid, and one turned out to be euthyroid. All three patients who were thyrotoxic at diagnosis turned to euthyroid status spontaneously in a few months. There was no statistically significant difference concerning the thyroid autoantibody levels and parenchyma echogenicity at the time of diagnosis and after follow-up, but TV decreased significantly during the follow-up period (p<0.001).
In the group of patients who received LT4 treatment, although parenchyma echogenicity and anti-Tg levels did not change significantly, TV and anti-TPO levels were significantly decreased (p<0.001) during follow-up period. After excluding the effects of thyroid autoantibodies, the mean TV of treated patients decreased significantly more than the untreated ones (p=0.002). In euthyroid and subclinically hypothyroid patients, LT4 therapy did not affect thyroid volume decrease.
A significant relationship between smoking at diagnosis and serum TSH level, anti-TPO level, TV, parenchyma echogenicity, nodularity was not found, but serum anti-Tg level was significantly higher in the smoking group (p=0.009).
Family history of AITD was not associated with initial serum TSH level, thyroid autoantibody level, TV, parenchyma echogenicity, and nodularity. Relationships among studied parameters at the time of diagnosis were summarized in Table 2.
Table 2.
Relationship between smoking, family history and study parameters at the time of diagnosis
| Smoking | Nonsmoking | p | Family history (+) | Family history(-) | p | |
|---|---|---|---|---|---|---|
| TSH(µIU/ml) # | 5.1(0.02-150.9) | 5.6(0.02-346.8) | 0.374 | 4.9(0.28-346.8) | 5.8(0.02-198.5) | 0.298 |
| AntiTPO(IU/ml) ¶ | 269(5.8-9181) | 330(4.4-6093) | 0.857 | 329.7(7.1-5282) | 280.(4.4-9781) | 0.733 |
| Anti-Tg (IU/ml) ¶ | 303(9.9-9186) | 113(2.2-7800) | 0.009* | 189.3(4.4-9186) | 126(2.2-7800) | 0.780 |
| Thyroid volume (ml)¶ | 15.6±11.5 | 16.4±9.4 | 0.374 | 17.1±10.6 | 15.5±9.6 | 0.443 |
| Parenchyma echogenicity(%) | ||||||
| Diffuse | 0% | 3% | 2.4% | 1.8% | ||
| Mildly hypoechogenic | 9.7% | 6% | 7.1% | 7.1% | ||
| Moderately hypoechogenic ¶ # | 45.2% | 34.3% | ¶0.349 | 35.7% | 39.3% | #0.822 |
| Severely hypoechogenic | 45.2% | 56.7% | 54.8% | 51.8% | ||
| Nodule (%) | 25.8% | 23.9% | 0.837 | 23.8% | 25% | 0.892 |
¶ Student’s T-test # Mann- Whitney U test * p<0.05 is statistically significant.
During the follow-up period, seven patients got pregnant and gave birth to a healthy child. All of them were in the group treated with LT4. When they were compared with the women who did not become pregnant, there was no statistically significant difference in thyroid autoantibody levels, TV, and parenchyma echogenicity.
The mean serum Se level was 75.29±16.12 µg/L, and there was no significant difference between treated and untreated groups. Serum Se levels were correlated negatively with only the parenchyma echogenicity in only treated patients (r= -0.629, p= 0.016). There was no correlation between serum Se levels and thyroid function tests, thyroid autoantibodies, TV, nodularity.
Logarithms of thyroid volumes showed a “Gaussian distribution” in all patients at diagnosis (Fig. 1a) (p=0.066) and at the end of the observation period, independent of receiving (Fig. 1b) and not receiving LT4 treatment (Fig. 1c).
Figure 1.
a. The logarithm of thyroid volume at diagnosis; b. The logarithm of thyroid volume in untreated patients; c. The logarithm of thyroid volume in treated patients.
Discussion
Although this study was not a prospective randomized controlled trial, it was still necessary to emphasize HT’s course in the adult population and the factors that could affect it.
The population-based studies revealed that the thyroid autoantibody levels increased with aging, especially in female patients. Pederson et al. showed that all the patients having subclinical hypothyroidism and atrophic thyroid gland were above 40 years of age (15). In this study, the age was not related to the thyroid autoantibody, TSH levels, and TV at diagnosis.
TSH levels at diagnosis showed a weak positive correlation with anti-TPO levels, whereas it was not related to anti-Tg levels, and this was in accordance with other broad participation studies (16). In opposition to the study of Takamatsu et al. (17), the thyroid autoantibody levels were not related to TV, parenchyma echogenicity, and nodularity in our study. The absence of correlation between the thyroid autoantibody levels and TV could be explained by Pederson et al., which demonstrated that this correlation was dependent on the increased levels of TSH (15). In our study, the median TSH was 5.22 mIU/L, so the absence of correlation between the thyroid autoantibody levels and TV could be due to relatively low TSH levels. Furthermore, a weak positive correlation between anti-TPO levels and TV in subclinically hypothyroid patients in this study supports this explanation. The absence of a similar correlation between the thyroid autoantibody levels and TV in overt hypothyroid patients could be due to the atrophy of the thyroid gland in 50% (n=7) of the patients.
In the study of Huber et al., TSH was found to have more predictive value than anti-TPO levels to estimate subclinical hypothyroidism’s transformation to overt hypothyroidism in HT patients (18). In this study, none of the subclinically hypothyroid patients progressed to overt hypothyroidism after a follow-up period of an average of 9.2 years. Although their anti-TPO levels were unexpectedly high, their TSH was below 6 mIU/L. This was compatible with the study of Huber et al., but it could also be due to the relatively short follow-up period.
In the previous studies, goiter prevalence was found to increase with smoking. Thiocyanate, present in the cigarette, could cause goiter by blocking the iodine uptake into the thyroid gland and organification. Benziprenine in tobacco could affect the thyroid functions by stimulating the sympathetic nervous system (19, 20). In NHANES III (21) study, smoking appears to be negatively associated with serological evidence of thyroid autoimmunity and hypothyroidism. In contrast, in a Chinese study (22), there was no difference in serum TSH and Tg levels between smokers and non-smokers, but the positivity of TPO-Ab (>100 IU/mL) was higher in smokers than in non-smokers. Although there was no relationship among smoking and TSH, anti-TPO levels, TV, parenchyma echogenicity, and nodularity, anti-Tg levels were significantly higher in smokers in our study. This finding might be due to the change in the antigenic structure of the thyroglobulin due to smoking.
Thyroid development and function may be impaired by deficiencies of several trace elements mainly iodine and selenium, iron, zinc, copper and calcium. Excess selenium intake aggravates consequences of iodine deficiency in endemic regions, whereas adequate selenium supply attenuates adverse effects of iodine excess on the thyroid gland, preventing inflammation, fibrosis and destruction. The thyroid tissue damage initiated by high TSH levels leads an enhanced production of H2O2, ROS and reactive oxygen intermediates, can be prevented by adequate selenium status. Serum selenium status was found in various levels in benign and malignant thyroid diseases, including AIT. Selenium status contributes to the HT by Th1-cell-associated thyroid destruction and Graves’ disease by Th2 induced hyperstimulation of the thyrocytes by TSH receptor autoantibodies (23).
The elevated selenium levels upregulates Th1 and regulatory T cells response, whereas selenium deficiency is associated with elevated Th2 cells and markers(24). Both in newly diagnosed Graves’ disease and HT, low selenium levels were observed but, correlations of selenium status with serum titers of thyroid autoantibodies (anti-tpo, anti-Tg) were inconsistent (23).
Several interventional studies showed that increased selenium intake with selenium supplementations had no impact on thyroid hormones, TSH serum concentrations and TPO antibody titers (25,26). In the study of Hagmar et al., no impact of Se status on T3 and T4 levels was also observed. The slightly negative correlation of selenium status with TSH levels might indicate a higher TSH secretion at low selenium status (27). Plasma Se concentration and plasma glutathione peroxidase activity (GPX3) were found interrelated with TSH and fT4 in the study of Zagrodzki et al. (28).
Furthermore, Se is reported to be inversely related to TV, risk of goiter, and hypoechogenicity in women, independently of other known risk factors, i.e., anthropometry, age, menopausal status, smoking habits, alcohol, or antioxidants. Low thyroid echogenicity accompanied lymphocytic infiltration in thyroiditis and was positively correlated with thyroid autoantibodies. In men, the odds for goiter occurrence did not reach statistical significance (29).
But, there were also diverse results showing that selenium supplementation may reduce levels of antithyroid antibodies, improve thyroid structure, autoimmune thyroid diseases and interleukin levels, improve thyroid metabolism, and clinical symptoms (30-32).
Particularly, a recent meta-analysis showed that Se supplementation effectively reduces serum anti- TPO levels at 3, 6, and 12 months and serum anti-Tg at 12 months in LT4-treated populations, but not in non-treated ones. However, no signifcant correlation between the baseline serum Se and the decrease in serum TPO-Ab level was demonstrated in LT4-treated patient (33).
In our study, serum Se levels were correlated negatively with only the parenchyma echogenicity in only treated patients, and there was no correlation between serum Se levels and thyroid function tests, thyroid autoantibodies, TV.
Unfortunately limited information is present regarding Se status in Turkey. Our group performed first one of these, and reported mild Se deficiency (i.e. 54.8±15.7 µg/L) in Ankara in the year 2000 (34). Later on, Giray et al. reported an overall mean value of plasma Se as 71±15 (28-114) µg/L from all geographical parts of Turkey in 2004 (35) and their value for Central Anatolia, where Ankara is placed was 71 ± 11 (51-96) µg/L.
Regarding Iodine status in general population in Turkey, epidemiological studies, from our group, proved that Turkey had become from a moderate to severely iodine deficient country to, borderline iodine sufficient country, after mandatory salt iodization initiated in 1998 (i.e. 1997 to 2007)(36, 37). The lack of knowledge about iodine status of the participants is a limitation of this study.
These different observations may be due to be done in areas of different iodine intake, in different groups of patients (for example in patients already treated with thyroid hormone or individuals with very different antibody titers), and obscure levels of basal selenium status (23).
To the best our knowledge, we believe that we do not have sufficient evidence that Se supplementation should be given to patients with AIT.
In general, HT has been classified in two forms as goitrous and atrophic (2). In a study from Denmark, in opposition to this data, it was found that the TV distribution in HT patients was not bimodal, but instead Gaussian (normal) (5). Similarly, we found that both at diagnosis and after the follow-up period, regardless of LT4 treatment, the TV’s logarithm followed a Gaussian (normal) distribution. Both studies indicate that AIT should probably be considered as an entity since the atrophic form is likely the consequence of the auto-destructive process. However, these results should be confirmed by extensive randomized controlled studies.
In conclusion, although this study was not a prospective randomized controlled trial, it was still necessary to emphasize that: thyroid volume decreases regardless of LT4 treatment in most patients with Hashimoto’s thyroiditis during the follow-up. The high anti-TPO level is associated with hypothyroidism. Thyroid autoantibody level is not associated with parenchyma echogenicity and nodularity. Serum Se levels were correlated negatively only with the parenchyma echogenicity and only in treated patients, and there was no correlation between serum Se levels and thyroid function tests, thyroid autoantibodies, and thyroid volume. Importantly logarithm of thyroid volumes do not follow a bimodal distribution as reported in the literature, but they follow a normal distribution regardless of LT4 treatment, and cases with thyroid atrophy and goiter are extremes within this normal distribution.
Conflict of interest
The authors declare that they have no conflict of interest.
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