Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat

Abstract

Amiodarone (AMD)-induced toxicity can be a life-threatening complication which limits the use of amiodarone as an anti-arrhythmic agent. The aim of the present study was to determine the nature of AMD toxicity by comparing ultrastructural changes induced by AMD and equivalent amounts of iodide in two animal models, the Wistar and the autoimmune BB/W rat. Rats were divided into control (water), AMD-(30 mg AMD/kg) or iodide-treated (10 mg/kg) groups. Thyroids were removed at 15 weeks and processed for electron microscopy.We found that AMD induced specific ultrastructural changes of thyroid cytotoxicity in both rat models, which were distinct compared with changes induced by excess iodide alone. Specific changes included marked distortion of thyroid architecture, evidence of necrosis and apoptosis, inclusion bodies, lipofuscinogenesis and markedly dilated endoplasmic reticulum (ER). Our data indicate that AMD is directly cytotoxic to the thyroid an effect mediated by disruption of subcellular organelle function. ER dilatation is suggestive that AMD cytotoxicity may be mediated through disruption of the protein sorting pathways leading to a drug-induced form of ER storage disease. The predilection of the thyroid to AMD may be explained by the additive effects of excess iodine and AMD drug toxicity on protein sorting pathways. European Journal of Endocrinology 137 89-98

Towards an animal model of amiodarone-induced thyroid dysfunction

“…The ultrastructural changes observed by Pitsiavas et al (8) in their rat model might also provide a clue to the nature of amiodarone-induced cytotoxicity. Amiodarone as an amphiphilic drug has a strong attraction for intralysosomal phospholipids, and the binding of the drug and these phospholipids renders them indigestible by phospholipases.…”

“…As indicated by Pitsiavas et al (8), their histopathological findings are akin to the severe follicular damage and disruption in surgical specimens of patients who underwent thyroidectomy because of AIT type II (15). As specimens from amiodarone-treated euthyroid patients reveal minimal or no thyroid follicular damage (16), one would expect some degree of thyrotoxicosis in the amiodarone-treated rats with marked follicular disruption.…”

“…In summary, the paper by Pitsiavas et al (8) has provided new evidence for a direct cytotoxic effect of amiodarone on the thyroid gland, which is different from that of iodine excess. Their findings are relevant for our understanding of the pathogenesis of AIT type II.…”

“…It is against this backgound that the paper of Pitsiavas et al in this issue of the Journal is of much interest (8). They studied ultrastructural changes in the thyroid gland of rats treated with amiodarone or with a comparable amount of sodium iodide.…”

“…From the results of Pitsiavas et al (8) it is clear that amiodarone treatment causes extensive damage to the thyroid gland far beyond that caused by equivalent doses of iodide. Amiodarone disrupts the architecture of the thyroid both at a cellular and subcellular level, and it is easy to visualize how amiodarone causes destructive thyroiditis.…”