Treatment of hyper- and hypothyroidism : Lugol’s iodine and liothyronine

Background Hyper- and hypothyroidism are commonly treated according to well- established guidelines. However, subsets of patients are treated with non- standard therapies. In hyperthyroid conditions, preoperative management with Lugol's iodine is occasionally used, while in autoimmune hypothyroidism, liothyronine is prescribed to selected patients with persistent symptoms despite adequate thyroxine treatment. The clinical impact, safety, and consequences of these non-standard treatment approaches remain incompletely understood. Objective The objective of this thesis was to evaluate non-standard treatments in thyroid disease, focusing on preoperative Lugol's iodine in hyperthyroid conditions and liothyronine in autoimmune hypothyroidism. Specifically, the aims were to assess clinical outcomes of preoperative Lugol's iodine in Graves' disease, evaluate the safety and tolerability of short-term Lugol's iodine in toxic nodular thyroid disease, examine the association between preexisting psychiatric morbidity and subsequent liothyronine use, and investigate psychiatric outcomes following liothyronine exposure in autoimmune hypothyroidism. Methods This thesis comprises four studies using different designs. Retrospective population-based observational studies and a prospective interventional study were conducted. Surgical outcomes following rescue preoperative Lugol's iodine were assessed using the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery in a regional cohort of patients undergoing thyroidectomy. The short-term safety and hormonal effects of Lugol's iodine in patients with toxic nodular thyroid disease were examined in an open-label pre-post intervention trial. Nationwide register-based retrospective cohort studies were used to investigate associations between psychiatric morbidity and liothyronine treatment in autoimmune hypothyroidism, including both predictors of liothyronine use and subsequent psychiatric outcomes after exposure to liothyronine. Data from the National Patient Register and the National Prescribed Drug Register were analyzed using regression and time-to- event models adjusted for key covariates. Results Preoperative Lugol's iodine was associated with an increased short-term need for calcium and active vitamin D supplementation following thyroidectomy; these differences did not persist at later follow-up. In patients with toxic nodular thyroid disease, short-term Lugol's iodine treatment resulted in reduced thyroid hormone concentrations without any signs of aggravated thyrotoxicosis or deterioration in quality of life. In the nationwide register- based analyses on liothyronine, preexisting affective or anxiety-related psychiatric morbidity was associated with an increased likelihood of subsequent liothyronine treatment in autoimmune hypothyroidism. Furthermore, liothyronine exposure was associated with an increased risk of later incident psychiatric morbidity, including affective or anxiety morbidity, and possibly psychotic morbidity, with consistent findings across most sex and age strata, except in individuals aged 75 years or older, where no associations were found. Conclusions This thesis highlights clinical considerations regarding non-standard treatments in thyroid disease. The findings support heightened postoperative vigilance when Lugol's iodine is used before thyroidectomy in a rescue setting and suggest that short-term Lugol's iodine may be a feasible preoperative option in toxic nodular thyroid disease when antithyroid drugs are unsuitable. In autoimmune hypothyroidism, the results underscore the importance of awareness of poor mental well-being and psychiatric vulnerability, both before and during treatment of this condition. List of scientific papers I. Surgical outcome after thyroidectomy due to Graves' disease and Lugol iodine treatment: a retrospective register-based cohort study. Hedberg F, Falhammar H, Calissendorff J, Bränström R. Endocrine. 2024 Jul;85(1):272-278. Epub 2024 Feb 2. PMID: 38306008 https://doi.org/10.1007/s12020-024-03708-4 Il. Assessing the Impact of short-term Lugol's solution on toxic nodular thyroid disease: A pre-post-intervention study. Hedberg F, Cramon PK, Bränstrom R, Falhammar H, Calissendorff F. Front Endocrinol (Lausanne). 2024 Jul 25;15:1420154. eCollection 2024. PMID: 39119004 https://doi.org/10.3389/fendo.2024.1420154 III. Influence of Preexisting Psychiatric Morbidity on Liothyronine Use in Hypothyroidism: A Swedish Nationwide Cohort Study. Hedberg F, Lindh JD, Mannheimer B, Planck T, Skov J, Lehtihet M, Falhammar H, Calissendorff J. J Clin Endocrinol Metab. 2025 Jun 7:dgaf337. Online ahead of print. PMID: 40482039 https://doi.org/10.1210/clinem/dgaf337 IV. Psychiatric Morbidity Following Liothyronine Exposure in Autoimmune Hypothyroidism: A Swedish Nationwide Cohort Study. Hedberg F, Lind JD, Mannheimer B, Planck T, Skov J, Falhammar H, Calissendorff J. [Submitted]