Hashimoto's Thyroiditis Affects Symptom Load and Quality of Life Unrelated to Hypothyroidism: A Prospective Case–Control Study in Women Undergoing Thyroidectomy for Benign Goiter

Abstract

Background:

Hashimoto's thyroiditis (HT) is a common disease, and is the most prevalent cause of hypothyroidism. Symptoms and diseases associated with HT are considered to be caused by hypothyroidism. We hypothesized that higher antithyroperoxidase (anti-TPO) antibody levels would be associated with an increased symptom load and a decreased quality of life in a female euthyroid patient collective.

Methods:

In a prospective cohort study 426 consecutive euthyroid female patients undergoing thyroid surgery for benign thyroid disease were included. Main outcome measures were preoperative anti-TPO levels, a symptom questionnaire and the SF-36 questionnaire, and lymphocytic infiltration of the thyroid tissue as evaluated by histology.

Results:

Histology revealed HT in 28/426 (6.6%) subjects. To maximize the sum of the predictive values, a cut-off point for anti-TPO of 121.0 IU/mL was calculated (sensitivity 93.3% [95% confidence interval: 77.9%–99.0%]; specificity 94.7% [95% confidence interval: 92.0%–96.7%]) to predict the presence of histological signs of HT. The mean number of reported symptoms was significantly higher in patients with anti-TPO levels >121.0 IU/mL than in the other group (6.7 ± 2.5 vs. 4.1 ± 2.8; p < 0.001). There were no differences in preoperative thyroid-stimulating hormone levels (1.7 ± 1.3 vs. 1.5 ± 1.4 μU/mL, respectively; p = 0.155). Chronic fatigue, dry hair, chronic irritability, chronic nervousness, a history of breast cancer and early miscarriage, and lower quality-of-life levels were significantly associated with anti-TPO levels exceeding the cut-off point (p < 0.05).

Conclusions:

Women with HT suffer from a high symptom load. Hypothyroidism is only a contributing factor to the development of associated conditions.

Introduction

C hronic autoimmune thyroiditis (Hashimoto's thyroiditis [HT]) is a common disease, and is the most prevalent cause of subclinical or overt hypothyroidism in areas with sufficient iodine intake (1). The disease is characterized by the presence of antithyroperoxidase (anti-TPO) antibodies.

Thyroid autoimmunity represents one of the most common autoimmune gender-specific disorders, and affects 5%–10% of the female population of childbearing age (2). It has been shown to be associated with various gynecologic problems. The clinical relevance of thyroid autoimmunity in infertility, classically defined as the inability to conceive after 1 year of intercourse without the use of contraception (3), remains controversial. Several studies have reported an association between thyroid autoimmunity and infertility (4 –7). In a pooled analysis, Poppe et al. calculated a highly significant (p < 0.0001) relative risk clearly associating thyroid autoimmunity with infertility (7,8). Further, many studies have shown that thyroid autoimmunity correlates with a significant increase in miscarriage rates (9 –12).

Thyroid autoimmunity has also been shown to affect quality of life, as measured by a short-form health survey with 36 questions (SF-36 questionnaire) (13). This is thought to be due to the fact that thyroid autoimmunity, as well as the associated hypothyroidism, leads to common symptoms, such as changes in body weight, exhaustibility, weakness, sensation of cold, low core temperature, dry skin and hair, and even psychical complaints, such as depression and irascibility (14,15).

To date, it is believed that the above-mentioned phenomena are related to the presence of hypothyroidism. However, in our experience, many patients who suffer from HT—even those who are well supplemented with thyroid hormones—experience phases of general indisposition associated with various symptoms. Thus, the main hypothesis of our prospective study was that higher anti-TPO levels would be associated with an increased symptom load and a decreased quality of life in a euthyroid patient collective.

Materials and Methods

The primary hypothesis was that general and female health-related symptoms and the overall quality of life were associated with the presence of HT, as measured by preoperative anti-TPO levels in euthyroid patients. This was based on the secondary study objectives: (i) evaluation of the prevalence of HT in our patient collective, including data on histological grading, and (ii) evaluation of an optimized preoperative anti-TPO cut-off value for the prediction of HT in the thyroid specimen.

As defined by the study protocol, all data were prospectively obtained and entered in a database. This included the symptom questionnaire, the SF-36 questionnaire, and the histological findings.

Study collective

We prospectively included a total of 426 consecutive patients based on the following inclusion criteria: (i) women who planned to undergo thyroid surgery, ≥19 years of age; (ii) women who had a thyroid-stimulating hormone (TSH) level within the institutional normal range (0.25–4.20 μU/mL) so that only euthyroid patients were included; and (iii) a parathyroid hormone (PTH) level within the institutional normal range (0–63 IU/mL). Patients with thyroid malignancies, as diagnosed by histology of the removed specimen, were excluded retrospectively.

Patients gave informed written consent, and all procedures were performed in accord with the “Good Scientific Practice Standards” set forth by the Medical University of Vienna, which are based on the ethics standards of the revised Helsinki Declaration of 2008. According to an official notification of the Ethics Committee of the Town of Vienna (EK 09-167-VK_NZ), the approval of the local ethics committee was not necessary.

Symptom questionnaire

All patients were asked to answer a questionnaire on general and female health on the day before surgery. The questionnaire comprised questions on general symptoms (chronic fatigue, dry skin, dry hair, chronic sensation of cold, frequent sweating, general feeling of chronic weakness, whether they became easily fatigued, dysphagia, chronic weeping, chronic irritability, chronic lack of concentration, chronic nervousness, or frequent mood swings) and female health (vaginal dryness; regularity of the menstrual cycle; premenstrual pain in the lower abdomen that required pain-killers; time interval since the last menstrual bleeding; gravidity; parity; number of early pregnancy losses, defined as the termination of pregnancy before 20 weeks' gestation; number of extrauterine gravidities; number of abortions; whether and how long the patient breastfed a child; infertility, defined as the failure to conceive after a year of regular intercourse without the use of contraception; or whether the patient had ever had breast cancer). In addition, patients were requested to answer the SF-36 quality-of-life questionnaire.

Determination of hemostatic variables

Preoperatively, serum levels of the following were measured: TSH, free thyroxine (fT4), free triiodothyronine (fT3), and anti-TPO antibodies using a chemiluminescent microparticle immunoassay (Elecsys 2010; Roche). The normal range of anti-TPO at our department is 0–63 IU/mL.

Antibodies against thyroglobulin (TG-Ab) were not part of the prospective protocol. However, since they were available in 180/426 (42.3%) of patients, they were included in the analysis.

Surgical technique

Patients underwent unilateral as well as bilateral thyroid operations, including subtotal, near-total, and total lobectomies/thyroidectomies. In all patients, sufficient material was excised to enable histological evaluation.

Histological examinations

As part of the prospective protocol, the whole thyroid parenchyma of the removed specimen was histologically examined. This comprised routine grading of thyroid inflammation severity and graded on a scale of 0–4 according to Williams and Doniach (16). HT was defined as a lymphocytic infiltration of grading 3 or 4. Scoring was performed by pathologists who were blind to the anti-TPO level.

Statistical analysis

Variables are described by frequencies, mean ± standard deviation or median, and interquartile range. Statistical analysis was performed using the unpaired and paired t-tests, the u-test, Fisher's exact test, or the chi-square test. Differences were considered statistically significant if p < 0.05. Statistical analysis was performed with SPSS 15.0.1 for Windows (SPSS Inc., 1989–2006).

We considered the histological finding the only reliable criterion for the predictive accuracy of preoperative anti-TPO levels. Thus, we did not use the institutional normal ranges. Instead, the optimal cut-off point of the predictive factors was calculated automatically based on the receiver–operator characteristic (ROC) curve with MedCalc™ (version 10.4.8.0) software as the threshold value with the highest specificity and sensitivity. Specificity describes the percentage of correct predictions in the group of patients with anti-TPO levels lower than the cut-off points for detecting histological signs of HT. Sensitivity described the percentage of correct predictions in the group of patients with anti-TPO levels higher than the cut-off points. Discriminatory ability correlates between specificity and sensitivity and is measured by the area under the ROC curve. All values are given with a 95% confidence interval (95% CI).

Results

Patient characteristics

A total of 426 female patients (age 54.5 ± 12.1 years, body mass index 27.1 ± 5.4 kg/m²) were included. One-hundred sixteen patients (27.2%) were in need for thyroid hormone supplementation before the operation. Preoperative hormone levels were as follows: TSH 1.6 ± 2.1 μU/mL, fT3 5.0 ± 1.0 pmol/L, fT4 1.3 ± 0.2 ng/dL, anti-TPO 50.5 ± 113.6 IU/mL, and TG-Ab 84.4 ± 283.0 IU/mL. Thirty-six patients (8.5%) were smokers. A total of 132 patients (31.0%) were found to suffer from any kind of comorbidity: arterial hypertension in 86 (20.2%), hyperlipidemia in 20 (4.7%), diabetes mellitus in 10 (2.3%), osteoporosis in 27 (6.3%), depression in 30 (%), chronic obstructive pulmonary disease (COPD) in 20 (4.7%), and coronary heart disease in 6 (1.4%) (multiple selections possible).

Histologic diagnosis of HT and prediction using anti-TPO level

Histology revealed thyroiditis grades 0, 1, 2, 3, and 4 in 256 (60.1%), 94 (22.1%), 48 (11.3%), 15 (3.5%), and 13 patients (3.1%), respectively. Thus, HT (grades 3 or 4) was found in 28/426 (6.6%) subjects. Patients for whom HT was found with histology showed significantly higher anti-TPO levels than those without histological signs of HT (367.4 ± 134.7 vs. 28.2 ± 65.7 IU/mL, respectively; p < 0.0001 with the u-test). Details are provided in Table 1. The level of anti-TPO antibodies was significantly correlated to thyroiditis grade (r ² = 0.46, p < 0.001).

Table 1.

Clinical Characteristics of Patients With and Without Histological Signs of Hashimoto's Thyroiditis

	No Hashimoto's thyroiditis (n = 398)	Hashimoto's thyroiditis (n = 28)	p-Value
Age (years)	55.1 ± 12.2	51.4 ± 11.2	0.291
BMI (kg/m²)	26.8 ± 5.1	27.7 ± 5.9	0.519
Preoperative TSH (μU/mL)	1.5 ± 1.4	1.7 ± 1.3	0.370
Preoperative fT3 (pmol/L)	5.1 ± 2.1	4.9 ± 1.0	0.544
Preoperative fT4 (ng/dL)	1.3 ± 0.4	1.2 ± 0.2	0.391
Preoperative anti-TPO (IU/mL)	28.2 ± 65.7	367.4 ± 134.7	<0.001^a
Preoperative TG-Ab (IU/mL)	9.3 ± 19.2	381.8 ± 282.8	<0.001^a
Patients with thyroid hormone supplementation (n, %)	105 (26.4)	11 (39.3)	0.138
Patients with comorbidity (n, %)	122 (30.7)	10 (35.7)	0.576
Smokers (n, %)	32 (8.0)	4 (14.3)	0.280

Statistically significant.

Anti-TPO, antithyroperoxidase; BMI, body mass index; fT3, free triiodothyronine; fT4, free thyroxine; TG-Ab, thyroglobulin antibody; TSH, thyroid-stimulating hormone.

The area under the curve of the ROC for HT using preoperative anti-TPO levels was 0.97 (95% CI: 0.95–0.99; p < 0.001). To maximize the sum of the predictive values, a cut-off point for anti-TPO of 121.0 IU/mL was calculated, with a sensitivity of 93.3% (95% CI: 77.9%–99.0%) and a specificity of 94.7% (95% CI: 92.0%–96.7%) to predict the presence of histological signs of HT. For 26/47 (55.3%) patients with anti-TPO >121.0 IU/mL histology revealed HT in contrast to 2/379 (0.5%) patients with anti-TPO ≤121.0 IU/mL.

For 21 patients (aged 51.1 ± 15.4 years) for whom anti-TPO levels above the cut-off point were found, HT was not seen during histologic examination (thyroiditis grades 0, 1, and 2 in 3 [14.3%], 5 [23.8%], and 13 [61.9%] cases, respectively). Their mean preoperative anti-TPO level was 265.1 ± 124.6 IU/mL. HT with anti-TPO levels <121.0 IU/mL were found for two women (aged 44 and 63 years). For these patients, the preoperative anti-TPO levels were 9.5 and 65.8 IU/mL.

Female and general health issues: comparative demographics

When patients with an anti-TPO below 121.0 IU/mL were compared with those with an anti-TPO above 121.0 IU/mL, no differences were found in the prevalence of menopausal patients (233/379 [61.5%] vs. 28/47 [59.6%], p = 0.801), of patients in need of supplementation with thyroid hormones (99/379 [26.1%] vs. 17/47 [36.2%], p = 0.144), of smokers (31/379 [8.2%] vs. 5/47 [10.6%], p = 0.577), or of patients suffering from arterial hypertension (74/379 [19.6%] vs. 12/47 [25.0%], p = 0.333), hyperlipidemia (19/379 [5.0%] vs. 1/74 [2.1%], p = 0.712), diabetes mellitus (9/379 [2.4%] vs. 1/74 [2.1%], p = 0.916), osteoporosis (25/379 [6.6%] vs. 2/74 [4.2%], p = 0.755), depression (27/379 [7.1%] vs. 3/74 [6.3%], p = 0.851), COPD (19/379 [5.0%] vs. 1/74 [2.1%], p = 0.712), or coronary heart disease (6/379 [1.6%] vs. 0/74 [0.0%], p = 0.385). There were also no differences in preoperative TSH levels (1.5 ± 1.4 vs. 1.7 ± 1.3 μU/mL; p = 0.155), fT3 levels (5.0 ± 1.7 vs. 5.2 ± 3.0 pmol/L, p = 0.497), and fT4 levels (1.3 ± 0.4 vs. 1.3 ± 0.5 ng/dL, p = 0.910). Patients had used thyroid hormone supplementation for 28.0 ± 18.9 and 31.2 ± 21.9 months in the group with an anti-TPO ≤121.0 IU/mL and in the group with anti-TPO >121.0 IU/mL, respectively (p = 0.209). Women with an anti-TPO above the cut-off point had had more pregnancies by trend (2.8 ± 1.8 vs. 2.0 ± 1.5; p = 0.058). Age at the time of surgery was similar in both groups (anti-TPO ≤121.0 IU/mL: 54.6 ± 12.0 vs. 52.3 ± 12.7 years, p = 0.092).

Anti-TPO levels and general health

With regard to general health, the results of the symptom questionnaire are given in Table 2. There were 26/379 patients (6.9%) with an anti-TPO lower than the cut-off point in contrast to 1/47 patients (2.1%) with anti-TPO levels exceeding the cut-off point who reported no symptoms (p = 0.340). The mean number of reported symptoms was significantly higher in patients with anti-TPO levels >44.8 IU/mL than in the other group (6.7 ± 2.5 vs. 4.1 ± 2.8; p < 0.001). For the following symptoms, significantly higher prevalence were found for patients with an anti-TPO level exceeding the cut-off point: chronic fatigue, dry hair, whether patients became easily fatigued, dysphagia, chronic irritability, and chronic nervousness.

Table 2.

Results of the Symptom Questionnaire

Symptom	Anti-TPO ≤121.0 IU/mL (n = 379)	Anti-TPO >121.0 IU/mL (n = 47)	p-Value
Chronic fatigue	185 (48.8%)	31 (66.0%)	0.027^a
Dry skin	168 (44.3%)	24 (51.1%)	0.381
Dry hair	77 (20.3%)	18 (38.3%)	0.005^a
Vaginal dryness	58 (15.3%)	8 (17.0%)	0.759
Chronic sensation of cold	82 (21.6%)	14 (29.8%)	0.207
Frequent sweating	165 (43.5%)	23 (48.9%)	0.482
Becoming easily fatigued	111 (29.3%)	21 (44.7%)	0.031^a
Chronic weakness	39 (10.3%)	7 (14.9%)	0.034^a
Dysphagia	63 (16.6%)	15 (31.9%)	0.011^a
Chronic weeping	86 (22.7%)	13 (27.7%)	0.447
Chronic irritability	95 (25.1%)	21 (44.7%)	0.004^a
Chronic lack of concentration	71 (18.7%)	15 (31.9%)	0.033^a
Chronic nervousness	149 (39.3%)	36 (67.6%)	<0.001^a
Frequent mood swings	110 (29.0%)	17 (36.2%)	0.312

Statistically significant.

When focusing on patients without thyroid hormone supplementation only (n = 310), similar results were seen for patients with anti-TPO >121.0 IU/mL. A higher mean symptom score (6.2 ± 3.7 vs. 4.3 ± 3.2, p = 0.003) was found as well as significantly higher prevalence of the following symptoms: chronic fatigue (14/30 [46.7%] vs. 79/280 [28.2%], p = 0.036), dysphagia (9/30 [30.0%] vs. 43/280 [15.4%], p = 0.041), chronic irritability (13/30 [43.3%] vs. 75/280 [26.8%], p = 0.028), and chronic nervousness (27/30 [90.0%] vs. 113/280 [40.4%], p < 0.001).

Anti-TPO levels were positively correlated with the symptom score, that is, the total number of symptoms per patient (r = 0.172; p < 0.001). This was also seen when the symptom score was subdivided into the following three groups: patients with less than or equal to two symptoms (n = 131; 30.8%), three to five symptoms (n = 141; 33.1%), and greater than or equal to six symptoms (154; 36.2%). Preoperative anti-TPO was highest in patients with six or more symptoms. The same was true for the body mass index. Details are provided in Table 3.

Table 3.

Associations Between Patient Characteristics/Hormone Parameters and the Symptom Score: Univariate Analysis

	Symptom score ≤2	Symptom score 3–5	Symptom score ≥6	p-Value
Anti-TPO (IU/mL)	8.0 (5.0; 14.2)	8.2 (5.3; 16.5)	10.0 (5.7; 55.3)	0.029^a
TG-Ab (IU/mL)^b	0.0 (0.0; 35.6)	0.0 (0.0; 17.9)	5.0 (0.0; 55.7)	0.127
TSH (μU/mL)	1.2 (0.7; 2.3)	1.0 (0.6; 2.3)	1.1 (0.7; 2.0)	0.972
fT3 (pmol/L)	4.6 ± 0.9	4.9 ± 0.9	5.1 ± 2.7	0.555
fT4 (ng/dL)	1.3 ± 0.3	1.3 ± 0.3	1.3 ± 0.4	0.797
Thyroid hormone supplementation (n, %)	22 (16.8%)	34 (24.1%)	33 (21.4%)	0.358
Age (years)	54.2 ± 13.1	54.5 ± 9.2	55.1 ± 13.2	0.324
BMI (kg/m²)	26.4 ± 5.3	27.0 ± 5.2	28.2 ± 5.9	<0.001^a
Hashimoto's thyroiditis in histology	6 (4.6%)	9 (6.4%)	13 (8.4%)	0.438

Statistically significant.

n = 180.

Anti-TPO levels and female health

In 15/146 premenopausal patients (10.3%) with an anti-TPO ≤121.0 IU/mL and in 2/19 premenopausal patients (10.5%) with an anti-TPO >121.0 IU/mL, infertility was found (p = 0.972). No differences were found for regular premenstrual pain in the lower abdomen that required pain-killers (anti-TPO ≤121.0 IU/mL: 58/146 [39.7%] vs. 7/19 [36.8%], p = 0.809).

There were 151/379 women (39.8%) with an anti-TPO ≤121.0 IU/mL and 20/47 women (42.6%) with an anti-TPO >121.0 IU/mL who had become menopausal spontaneously. Age at menopause was significantly higher in patients with anti-TPO levels above the cut-off point (47.6 ± 6.8 vs. 50.0 ±5.4 years, p = 0.045).

A history of breast cancer was reported by 3/47 women (6.4%) with an anti-TPO >121.0 IU/mL, in contrast to 10/379 women (2.6%) with an anti-TPO ≤121.0 IU/mL (p = 0.163).

Considering only those patients who had ever been pregnant, an anti-TPO exceeding the cut-off point was associated with a higher percentage of patients who had ever experienced at least one early pregnancy loss (16/39 [41.0%] vs. 67/302 [22.2%], p = 0.010).

Anti-TPO levels and quality of life

Higher anti-TPO levels were associated with a lower quality of life. Table 4 provides details on the results of the SF-36 questionnaire. Significantly lower (p < 0.05) quality-of-life scores were found for the following health parameters: general health, physical activity, vitality, social functioning, and mental health.

Table 4.

Quality of Life as Measured by the SF-36 Questionnaire

Health concept	Anti-TPO ≤121.0 IU/mL (n = 346)	Anti-TPO >121.0 IU/mL (n = 78)	p-Value
General health	68.2 ± 17.6	61.3 ± 22.6	0.015^a
Physical functioning^b	82.2 ± 20.8	75.9 ± 22.5	0.062
Role physical^c	80.3 ± 31.6	68.2 ± 37.1	0.011^a
Bodily pain	80.3 ± 23.8	74.7 ± 22.6	0.137
Vitality	57.0 ± 18.5	50.5 ± 17.3	0.025^a
Social functioning	82.3 ± 20.8	74.4 ± 21.6	0.020^a
Role emotional	80.2 ± 33.5	78.8 ± 31.4	0.798
Mental health	66.8 ± 18.0	61.7 ± 20.3	0.050^a

Statistically significant.

Ability to do daily activities.

Role limitations due to physical health.

Similar results were seen when analyzing patients without thyroid hormone supplementation: patients with anti-TPO levels ≤121.0 IU/mL revealed higher quality-of-life levels in the domains of general health (72.4 ± 14.3 vs. 61.8 ± 20.9, p = 0.027), role physical (81.8 ± 25.4 vs. 66.5 ± 28.5, p = 0.030), vitality (56.6 ± 14.8 vs. 48.2 ± 14.1, p = 0.041), and social functioning (84.5 ± 21.1 vs. 71.2 ± 19.6, p = 0.039).

Discussion

In this prospective study of 426 women with benign euthyroid goiter, increased anti-TPO levels were found to be associated with a lower quality of life and various general symptoms.

Anti-TPO is known to be strongly associated with the presence of thyroid autoimmunity (17). Our data prove that anti-TPO levels are predictors of the presence of HT, as diagnosed by histology, with sensitivity 93.3% and a specificity of 94.7% at the optimized cut-off level of 121.0 IU/mL. Only two patients with grade 3 were missed by our self-defined anti-TPO cut-off level. Thus, we consider that patients with anti-TPO levels >121.0 IU/mL are likely affected by HT. This is of importance for clinical routine, since patients might be treated for HT with selenium supplementation based on anti-TPO levels (14,15).

In our female study collective, we could demonstrate that the following general symptoms were associated with higher anti-TPO levels: chronic fatigue, dry hair, whether patients became easily fatigued, dysphagia, chronic irritability, and chronic nervousness. Therefore, it is not a surprise that higher anti-TPO concentrations were also associated with decreased quality-of-life levels. For various health parameters of the SF-36 questionnaire, differences between patients with lower and higher anti-TPO levels were found, including social functioning, vitality, and general health as the most affected parameters. Obviously, this reflects an altered health perception and is likely due to the higher symptom load.

A greater prevalence of a history of early pregnancy loss before the 20th gestational week was found for women with anti-TPO levels above the cut-off point. This is in accordance with another study by Negro et al., who concluded that euthyroid pregnant women, positive for anti-TPO, developed impaired thyroid function during pregnancy, which then was associated with an increased risk of miscarriage and preterm delivery, and that substitutive treatment with levothyroxine was able to lower the risk (18). This was, however, not confirmed by Tierney et al. (19).

Typically, symptoms, complications, and other diseases associated with HT are considered to be caused by hypothyroidism, and thus, it might be argued that hypothyroidism would account for the increased rates of symptoms and the lower quality-of-life scores in women with higher anti-TPO levels in our study, as well. However, at the time of inclusion, all patients were euthyroid indicating that overt hypothyroidism was not the cause for the higher symptom load and the lower quality-of-life scores in the group of patients with increased anti-TPO levels. Moreover, similar results in regard to quality of life and general symptoms were found, when only patients without thyroid hormone supplementation were analyzed.

About 30% of patients were in need of thyroid hormone supplementation in both groups (patients with anti-TPO levels ≤121.0 and >121.0 IU/mL). However, it is well known that thyroid hormone levels fluctuate widely in patients who suffer from HT, thus making it difficult to adjust the dosage of hormonal replacement. Therefore, the fact that patients with anti-TPO levels >121.0 IU/mL had experienced phases of temporary hypothyroidism more often than patients with anti-TPO ≤121.0 IU/mL cannot be ruled out. Further, HT is known to be a chronic disease that progressively destroys the thyroid gland over years, slowly leading to hypothyroidism which, at the beginning, might be latent or not immediately recognized by the patients (20). Thus, we cannot rule out that the significant association of a history of early pregnancy loss with higher anti-TPO levels in our study collective might have contributed to earlier phases of hypothyroidism. In addition, it might be argued that the prevalence of subclinical hypothyroidism, known to be common in patients who suffer from HT (21), was higher in patients with anti-TPO levels >121.0 IU/mL. Further, pernicious anemia is known to be associated with autoimmune thyroiditis, although it is believed to be caused by hypothyroidism (22).

However, especially symptoms like chronic nervousness and chronic irritability are not typically related to hypothyroidism or anemia. With this study, we are the first to demonstrate that patients with elevated anti-TPO levels suffer from a variety of general symptoms and a lower quality of life despite euthyroidism. These findings are of striking relevance since they shed new light on the clinical picture of HT.

Another factor possibly contributing to Hashimoto-related health conditions might be selenium. As mentioned above, selenium supplementation leads to a decrease in anti-TPO levels (14,15). Further, it displays antioxidant activity, anti-inflammatory, chemopreventive, and antiviral characteristics, and is also known to directly influence immune responses through its incorporation into selenoproteins (23). Moderate selenium deficiency has been associated with many conditions, such as increased risk of cancer and infections, male infertility, increased thyreocyte damage, and serious neurological diseases, including Alzheimer's and Parkinson's disease (24). It has already been stated that selenium deficiency might contribute to Hashimoto-related health conditions, especially to changes of mood, behavior, and cognitive function. Again, subclinical hypothyroidism has been considered a possible mechanism for these phenomena (25).

When focusing on female health issues, there was one quite surprising finding: in our dataset, the presence of elevated anti-TPO levels was associated with a higher age at menopause. This is in contrast to the study of Massoudi et al. (26), which reported that antibody levels did not differ at all based on menopausal status or hormone therapy use. However, anti-TPO antibodies might be the result of fetal microchimerism, that is, fetal cells passing into the maternal circulation during pregnancy. These cells could cause an antibody reaction and thereby lead to the development of anti-TPO autoantibodies. Thus, the anti-TPO level would be some kind of a surrogate parameter for former pregnancies, which are known to be associated with a higher age at menopause (27). In our data, higher anti-TPO levels were associated with a higher gravidity by trend, which supports this hypothesis.

We consider the following points as the strengths of our prospective study. We included a large patient collective (>400 women) and combined the SF-36 questionnaire with a symptom questionnaire. In addition, we were able to verify, in our own study collective, that anti-TPO was a predictive marker for the presence and for the severity of histologically confirmed HT. However, we did not routinely include TG-Ab that are also known to be associated with HT (28), since this is not routine clinical practice at our department. Moreover, only patients selected for thyroid surgery and thus suffering from some kind of thyroid diseases were included, which might be a confounder of the study. This is also represented by the fact that even of those patients without lymphocytic infiltration of the thyroid and those with thyroiditis grades 1 and 2, nearly 90% reported at least one symptom from the questionnaire on general health. We consider these factors weaknesses of our trial.

In conclusion, our study demonstrates higher rates for several symptoms, especially those that relate to mood, and lower quality-of-life levels for women with higher anti-TPO concentrations. Further, higher anti-TPO levels were associated with medical histories of breast cancer and early pregnancy loss. Since all of our patients were euthyroid at the time of inclusion into the study, and rates of symptoms for patients who were receiving thyroid hormone supplementation were similar to those of women with anti-TPO levels higher and lower than the cut-off point, we believe that hypothyroidism is only a contributing factor to the development and the presence of these associated symptoms and diseases, as well as to the decreased quality of life in patients with HT. Women with HT suffer from a relatively high symptom load. Further research is warranted to improve or develop treatment strategies.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist.

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