In vitro studies on the mechanisms of inhibited thyroidal iodide uptake and destructive thyroiditis as adverse effects of amiodarone and interferon-gamma

Abstract: The clinical use of the potent anti-arrhythmic drug amiodarone is limited due to adverse effects e.g. in the thyroid comprising both hypo- and hyperthyroidism. Amiodarone-induced thyroid dysfunction can occur in subjects with normal thyroid glands but also in those with an underlying thyroid abnormality resulting in an aggravation of the condition. Hashimoto´s thyroiditis and the presence of autoantibodies are common risk factors for developing amiodarone-induced hypothyroidism (AIH), it is though not known whether the thyroid effects of amiodarone can be modulated by the present immunologic activity or vice versa. In amiodarone-induced thyrotoxicosis (AIT), the thyroid iodide uptake is low thereby excluding 131I as a treatment of choice. This is suggestively caused by the cytotoxic effect of the drug resulting in a destructive thyroiditis with leakage of colloid content including preformed thyroid hormones and radioiodide. The thyroid epithelial integrity can also be impaired by proinflammatory cytokines. The aim of this thesis was to analyze the effect of amiodarone on the transepithelial transport of iodide and the effect of the major proinflammatory cytokine interferon-gamma on the thyroid epithelial barrier function. The maintenance of epithelial integrity is a prerequisite for the polarized thyroid phenotype that in turn enables the directed transport and lumenal concentration of iodide. Primary cultures of pig thyrocytes were seeded on filter in a bicameral chamber system thereby allowing the in vivo epithelial characteristics to be maintained and also to enable the simultaneous but separate monitoring of the transport of the tracer 125I- at the basolateral and apical plasma membranes. In the presence of amiodarone, the apical iodide permeability was reduced, an effect that was long-lasting and independent of cAMP and the iodine-content of the drug. Prior to the loss of epithelial barrier function induced by high doses of amiodarone, endocytosis from the apical domain was reduced and vacuoles of varying sizes were present in the cytoplasm. There was also a change in mitochondrial structure and function; a fission-like mitochondrial pattern and a biphasic effect on the membrane potential (hyperpolarization followed by depolarization), all being early pro-apoptotic signs. Interferon-gamma was shown to impair the epithelial barrier function in primary cultures of human thyrocytes, an event that was concomitant with the down-regulation and changed localization of the tight junction protein claudin-1. In conclusion, we suggest that the failure of the amiodarone-treated glands to concentrate radioiodide can be caused by a reduced apical iodide permeability and that the cytotoxic effect of amiodarone eventually causing apoptosis and loss of epithelial integrity can be a mechanism for the follicular destruction seen in AIT. The loss of epithelial barrier function by interferon-gamma might be a mechanism for exposure of hidden autoantigens to the immune system.