Hashimoto's disease, also known as chronic lymphocytic thyroiditis, is an autoimmune disease. Chronic lymphocytic thyroiditis is more common in middle-aged people but it can also affect people in any age group. The incidence rate of females is significantly higher than that of males, and the proportion of females to males is about 20:1. The onset is hidden and slow. It is often unintentionally found that the goiter is larger than usual. A small number of patients may have local discomfort or even pain, which is easily confused with subacute thyroiditis. The pathological features are moderate diffuse lymphocyte infiltration of the thyroid gland, and the formation of lymphoid follicle, plasma cell infiltration and rupture of the follicular follicle. Some follicular cells exhibit swelling and eosinophilia, the so-called “Askanazy cells”. Some patients may be associated with myxedema, the thyroid gland is small, or even inaccessible, and the changes in the thyroid histology is similar to the above ones, but the fiber changes significantly and the cell infiltration decreases. In addition, Hashimoto’s thyroiditis has a genetic predisposition, but if the condition of Hashimoto’s thyroiditis is controlled during pregnancy, it is generally possible to avoid passing on Hashimoto’s thyroiditis to the next generation.
The development of Hashimoto’s disease has gone through three stages. In the hyperthyroidism period, the patient has only mild hyperthyroidism symptoms, such as good appetite, easy tiredness, mild insomnia, and irritability. After repeated destruction of the thyroid tissue, the cells with normal functions are gradually reduced, and when the degree is reduced to a certain extent, the symptoms of mid-term hypothyroidism appear. When the secreted thyroxine is further reduced, it will be a clinically manifestation of late hypothyroidism.
Thyroid dysfunction patients generally use thyroid hormone replacement therapy, but thyroid hormone replacement therapy will affect general health for a long time. To date, randomized controlled trials have failed to demonstrate any benefit to general health status with L-thyroxine/T3 combination therapy. In addition, it also indicates the difficulty in designing clinical trials for therapeutic drugs, which is why you need an experienced and professional team to help you with innovation in experimental design and management.
Case Study
In most clinical trials, the recruitment of trial patients is often the primary difficulty. In order to obtain reliable and statistically significant experimental data, it is important to recruit a sufficient number of patients and control populations that meet the experimental requirements. Second, the judgment indicators of the experimental results should be formulated according to the purpose of the experiment. Previous studies have shown that the intrinsic defects of thyroid hormone replacement therapy may affect the patient’s neurocognitive function. Our experimental strategy uses a reasonable evaluation system for the experiment. The patient’s cognitive function is assessed by routine biochemical tests combined with neuropsychological tests, and the HADS questionnaire is used to assess whether there is depression.
Another challenge in clinical trials is the statistical analysis of data, which has many medical statistical methods, each applicable to different data. The statistical methods used in clinical trials must be carefully selected based on the data. In the report we report descriptive statistics for continuous variables as mean ± standard deviation. Non-normally distributed data is reported as the median (range). Semi-quantitative or categorical data is reported in proportion. We performed an ANOVA analysis to compare the average of the four subgroups of participants. Part of the correlation is used to discover important associations. All tests were performed using the SPSS software (version 17.0, SPSS Inc., Chicago, IL).
Using the above strategy, we recruited appropriate patients to evaluate the neurocognitive function (cognition, mood (depression and anxiety), and overall well-being (HRQOL) of the patients with primary hypothyroidism who were treated with long-term levothyroxine replacement therapy.
Design:
Double-blind and parallel group trials, including complete eligibility criteria, data collection schedules, and detailed statistical analysis.
Participants:
We recruited 130 patients with primary hypothyroidism from the Endocrinology, Diabetes and Metabolic Disease Clinic in the Serbian Clinical Center. In addition, we included 111 normal thyroid health controls (friends of patients without any endocrine, neurological or psychiatric disorders).
All Recruited Patients Met Requirements as Follows:
- Had clinical signs and laboratory findings of overt hypothyroidism before introduction of levothyroxine therapy.
- Had positive TPOAbs and/or TgAbs.
- Exclusion criteria were pre-existent neurological, psychiatric and other endocrine diseases. Both patients and controls were subjected to a full medical history (including past medical history and family history-patients denied other medical comorbidities), biochemical and full hormonal analysis, neurological (including psychiatric) examination, neuropsychological testing and evaluation of general well-being.
- Written and informed consent was obtained from all subjects. Study was approved by the Ethic Committee of Clinical Centre of Serbia.
Interventions:
The average age was 50.12±13.93 years (age 20-75 years old, 90% female, N=117), and long-term application of levothyroxine replacement therapy, mean 5.5±2.5 years old. The subjects were divided into two groups according to their age: 20 to 49 years old (N=59 vs N=79) and >50 years (N=71 vs N=32).
Main Outcomes:
Biochemical evaluation:
- Serum TSH levels were measured by immunoradiometric assay.
- FT4, FT3, and anti-thyroid peroxidase antibodies—TPOAbs、anti-thyroglobulin antibodies—TgAbs were measured by radioimmunoassay.
Neuropsychological test:
- Cognitive screening (MMSE, visual and digital breadth)
- Visual and linguistic attention span (WAIS and visual breadth)
- Concept tracking (TMT A-B), verbal divergent thinking (e.g. phoneme fl)
- The Anxiety and Depression Scale (HADS) assesses depression and anxiety.
Results:
Mean duration of hypothyroidism and levothyroxine replacement in patients was 5.54 ± 2.45 years. Mean levothyroxine dosage was 1.06 ± 0.60 mcg/kg. Both patient groups had higher levels of antibodies (TPOAb 2446.67 ± 273.36 vs 28.18 ± 11.71 and 2654.12 ± 300.38 vs 80.51 ± 23.00 and TgAb, 306.00 ± 88.06 vs 15.67 ± 22.97 and 235.38 ± 62.57 vs 32.79 ± 44.66 respectively), and serum TSH (3.64 ± 2.74 vs 1.93 ± 1.10 and 3.93 ± 2.84 vs 1.91 ± 0.90) when compared to controls, while serum FT4 (12.66 ± 2.87 vs 13.22 ± 2.97 and 12.11 ± 3.15 vs 11.02 ± 1.49), and FT3 (2.45 ± 0.46 vs 2.45 ± 0.64 and 2.33 ± 0.49 vs 2.54 ± 0.52) levels were not different. TSH was within the reference ranges in all groups (Table 1).
Table 1. Descriptive statistics in the subject subgroups
Neuropsychological results (Table 2): the average MMSE score in the control group was significantly higher than that in the patient group (p < 0. 05). The scores of TMT-A and TMT-B (Conceptual tracking) were much higher than those in the control group (p < 0. 05), except for the TMT-B in the young group (p < 0. 05). There was no difference between visual attention span (WMS-vizR, oral attention range (WMSverR) and attention index (WMSIP). The score of the speech diver’s thinking (fluency test) was far higher in the young group than in the control group (p=0.005), while the control group scored substantially higher in the fi classification than in the control group (p=0.005). The degree of depression in patients with fi was a lot higher than that in the control group (p<0.001), while that in the younger group was higher (p<0.05). The health-related quality of life (SF-36) score was enormously higher in the control group than in the treatment group (only in the A dimension - physical health and total score, p< 0.001).
Table 2. Neuropsychological tests in the subject subgroups
*MMSE mini mental state examination TMTA Trail Making Test A, TMTB Trail Making Test B, WMSIP WMS attention index, WMSvizR WMS visual span, WMSverR WMS verbal span, KF categorical fluency, FF phonemic fluency, HADSA hospital anxiety and depression scale—Anxiety, HADSD hospital anxiety and depression scale—Depression, PF physical functioning, RP physical role playing, BP bodily pain - BP, GH general health, VT vitality, SF social functioning, RE emotional role playing, MH mental health, RH subjective health assessment, A-PH dimension A-physical health, B-MH Dimension B-mental health, SF-36 Short Form Health Survey *P < 0.05; **P < 0.001.
We used partial correlations to find potential associations among thyroid hormones (TSH, FT4 / FT3) and antibodies (TPOAb, TgAb) and cognitive function, attention, anxiety, depression, and QoL (Table 3, 4). There was a negative significant correlation between antibodies (TPOAb, TgAb) and quality of life (total SF36 score). Depression correlated both with TSH levels and the levels of TPOAb.
Table 3. Association of neuropsychological tests with hormonal status (partial correlations adjusted for age, education, BMI, HADSA and HADSD)
Table 4. Association of anxiety and depression with hormonal status in participants (partial correlations adjusted for age, education, BMI)
*BMI body mass index, TSH thyroid-stimulating hormone, FT4 free thyroxine, FT3 free-triiodothyronine, antiTg thyreoglobulin antibodies, antiTPO thyroid-peroxidase antibodies, HADSA hospital anxiety and depression scale—Anxiety, HADSD hospital anxiety and depression scale—Depression *P< 0.05; **P< 0.001.
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References:
1. Djurovic, M., et al. (2018) ‘Cognitive functioning and quality of life in patients with Hashimoto thyroiditis on long-term levothyroxine replacement’, Endocrine, 1-8.
2. Leyhe, T., Mussig, K. (2014) ‘Cognitive and affective dysfunctions in autoimmune thyroiditis’, Brain Behav Immun, 41, 261-266.
3. Bauer, M., et al. (2008) ‘The thyroid-brain interaction in thyroid disorders and mood disorders’, Neuroendocrinol, 20(10), 1101-14.
4. Giannouli, V., et al. (2014) ‘Cognitive function in Hashimoto's thyroiditis under levothyroxine treatment’, Hormones (Athens), 13(3), 430-433.