Expert Commentary & Five-year View
HT is certainly a matter of high clinical relevance, even when thyroid gland function is normal. With no doubt, a group of HT patients with normal TSH levels do not report any symptoms. However, many are affected by several conditions accompanying HT. In the future, the symptoms associated with HT will become increasingly important, owing to the fact that the incidence of HT has increased over the last several decades and this increase is expected to continue. The reasons are unclear. In addition to radiation exposure, increased iodide intake has been linked to the development of autoimmune thyroiditis, which is thought to have pleiotropic effects on various metabolic or immunological processes.
One of the main questions is whether euthyroid patients who suffer from symptoms related to HT can find medical help. A recent trial suggested that the majority of HT patients with significant symptoms appear to benefit from thyroidectomy. Symptoms such as a subjective feeling of compression, voice problems and tightness in the neck are especially likely to re-appear after thyroidectomy. Whether other symptoms such as mood disorders or chronic fatique could diminish after thyroidectomy remains open. Thyroid hormone levels fluctuate widely in patients who suffer from HT, making it difficult to adjust the dosage of hormonal replacement. Patients who suffer from HT might experience recurrent phases of temporary hypothyroidism. Complete removal of the thyroid gland would lead to severe overt hypothyroidism and would leave the patient in need of constant thyroid hormone substitution. Thus, the patient could be relieved from associated conditions that might be related to difficulties in thyroid hormone supplementation. Moreover, thyroidectomy likely reduces the antibody load. It has been mentioned that thyroid autoimmunity itself could contribute to various associated conditions, among which are primarily other autoimmune diseases. From a variety of hypotheses about the association between HT and systemic autoimmune diseases, one of the most feasible explanations seems to be a polyclonal autoimmune response against organ-specific autoantigens. Biró et al. demonstrated that specific haplotypes were associated with various autoimmune syndromes as well as with thyroid autoantibodies cross-reacting with several tissues; and that an unbalanced proinflammatory cytokine setting was characteristic of various autoimmune syndromes. However, the treatment approach of thyroid surgery might be considered quite radical and further studies need to be conducted.
Another treatment option could be selenium supplementation. However, the literature on its efficacy is contradictory. The thyroid gland is one of the human tissues with the highest selenium content. Selenoproteins involved in cellular antioxidative defense systems and redox control including the glutathione peroxidase and the thioredoxin reductase family, are involved in protection of the thyroid gland from excess hydrogen peroxide and reactive oxygen species produced by the follicles for biosynthesis of thyroid hormones. The three key enzymes involved in activation and inactivation of thyroid hormones – that is, the iodothyronine deiodinases 1, 2 and 3 – are selenoproteins with cell- and pathology-related expression patterns. Accordingly, selenium deficiency could contribute to decreased subjective well-being in HT patients due to increased local inflammation and/or subclinically altered thyroid hormone levels. As reported in a recent meta-analysis on selenium supplementation in patients with HT, participants assigned to selenium supplementation had a significantly higher chance of reporting an improvement in well-being and/or mood compared with controls. Thyroid function was generally found unaltered after selenium supplementation. However, no data on the demands in levothyroxin replacement therapy were recorded. Thus, selenium might act through a reduction in thyroid inflammation. Whether selenium might lead to improvements in subjective well-being only in selenium-deficient patients remains open.
Prophylactic levothyroxine treatment of euthyroid patients with HT has been shown to reduce both serological and cellular markers of autoimmune thyroiditis and to increase thyroid volume. In addition, thyroid-derived B lymphocytes were also demonstrated to decrease significantly, indicating immunologic changes. Therefore, such treatment might be considered useful to stop the progression or even manifestations of the disease. Without any doubt, levothyroxine treatment would relieve the patient from possible subclinical hypothyroidism, known to be common in patients with HT and mentioned as a causative factor. One might consider that the majority of HT-associated conditions could be related to subclinical hypothyroidism. This hypothesis is supported by the fact that even patients with low but measureable titers of anti-TPO have a high symptom load when TSH is within the upper normal range, indicating an incipient thyroid dysfunction. However, there is a lack of data on the possible clinical long-term benefits of prophylactic levothyroxine treatment in euthyroid HT patients. Furthermore, no recommendations on target TSH levels that should be achieved in the course of prophylactic levothyroxine treatment can be made at present.
Dehydroepiandrosterone (DHEA) might also be a possible future treatment option for patients with HT. DHEA has been found to be beneficial in the treatment of autoimmune diseases, and to reduce natural killer cell activity. In patients with systemic lupus erythematosus, it leads to a modest but clinically significant improvement in health-related quality of life measured by Patient Global Assessment. DHEA treatment has also been shown to provide anti-inflammatory benefits in rodent models of rheumatoid arthritis. Moreover, it can be useful in premature ovarian insufficiency by improving pregnancy rates and reducing miscarriage rates in advanced maternal age. It has also been shown to have a protective role against cancer including breast cancer, hepatoma, prostate cancer and myeloma among others, which is thought to be due to its strong antiproliferative effect and inhibition of migration of cancer cell lines when given in therapeutical doses.
In the next few years, further research will need to clarify the main pathophysiologic implications of thyroid autoimmunity and establish treatment options for all patients who suffer from HT.