Advances in the Understanding of Genomic Links Between Thyroid Dysfunction and Psychiatric Disorders

Thyroid Function Parameters

Thyroid function parameters have been suggested to affect the brain directly. However, conflicting results exist, and extensive population-based studies emphasize that a cross-sectional measurement of thyroid function variables does not correlate to QoL or psychiatric disease. ^4,5 This study concludes that the correlation between hypothyroidism and mood/anxiety disorder is not genetically mediated through thyroid hormone. Still, it cannot be ruled out that the initial severity of hypothyroidism, time to diagnosis, or periods of over- or undertreatment could play a role in each patient's QoL or risk of psychiatric disease.

Treatment Bias

Treatment bias could be part of the explanation, as thyroid function levels are measured in almost every patient having psychiatric symptoms or complaining of impaired well-being (i.e., tiredness). For the past 20 years, the number of patients treated with thyroid hormones has increased, which is related to a decrease in the TSH treatment threshold at the initiation time ^6,7 (even treating patients having normal thyroid function parameters). Recent studies indicate that up to one third of the treated patients do not need treatment. ⁸ By this, a substantial rate of overdiagnosis of hypothyroidism is present.

Overdiagnosis of hypothyroidism could bias the data used in the previous GWAS data as well as this study focusing on genetic correlations between thyroid disease and psychiatric disease.

Thyroid Autoantibodies

Thyroid autoantibodies, that is, thyroid peroxidase antibodies (TPO-Ab), have been claimed to be the explanation. Some centers even suggest total thyroidectomy to reduce the level of TPO-Ab and conclude from nonblinded studies that this can cure the symptoms. ⁹ However, population-based studies do not demonstrate a correlation between TPO-Ab and QoL or depression. ^{10 –12}

The authors state that almost all hypo- and hyperthyroid patients have an autoimmune disease. The phenotypes of hypo- and hyperthyroidism in this study are based on a combination of 10th revision of the International Statistical Classification (ICD10) codes and self-reported information on medication or having hyper-/hypothyroidism. In this study, they do not report any data on autoimmunity (i.e., TPO-Ab, thyroglobulin antibodies or TSH receptor antibodies), and the patients having nonautoimmune thyroid dysfunction could possibly dilute the data.

The authors speculate that more general autoimmunity is the explanation for these findings, but still we do not have an explicit correlation between thyroid autoimmunity in general and psychiatric disease.

Genetic Explanations

In recent years, the focus has been on the possible risk genes in hypothyroid patients, intending to detect vulnerable patients needing special care. ¹³

Previous studies have shown inconsistent results, as minor studies describe a correlation between specific single nucleotide polymorphisms (SNPs) (i.e., the deiodinase two genes) and decreased QoL; as a possible correlation of lower QoL due to low intracellular triiodothyronine (T3) levels. Testing for these SNPs could be a way of selecting patients needing an individual therapeutic approach. ¹³

Soheili-Nezhad et al reported genetic “hotspots,” indicating a coheritability between autoimmune thyroid disease with anxiety and depression. But after excluding these “hotspots” from the analysis, the correlation persisted. The authors conclude that explanations other than single genes/hotspots need to be investigated to fully understand the pathogenesis of the correlation between hypothyroidism and psychiatric disease. A genetic correlation between QoL in general and single genes/hotspots was not investigated in this study.

Medical Treatment

Medical treatment of hypothyroidism using only LT4 has been suggested as being the reason for poor QoL and an increased risk of psychiatric disease, as the normal human thyroid produces T3 as well as T4. ¹⁴ This implies that a supplement of T3 is needed to maintain the physiological levels of T3. Studies have demonstrated that a high dose of LT4 will induce hypothalamic feedback and, by this, downregulate deiodinase 2, and further decrease T3 levels. ¹⁵

A meta-analysis of 18 clinical trials has not shown a consistent benefit of combination therapy with LT4 and liothyronine. ¹⁶ Despite this evidence, combination therapy is widely used, and patient reports of treatment benefit continue to generate interest among patients and physicians. ¹³

In conclusion, the explanation of the increased risk of psychiatric disease and persistent symptoms in LT4-treated hypothyroid patients is still missing. However, this article, ¹ evaluating almost half a million patients, eliminates that the explanation is found in genetic “hotspots” pinpointing vulnerable patients. This study also indicates that the serum level of thyroid hormone does not mediate the association between thyroid dysfunction and the psychiatric diseases of anxiety and depression.