Ultrastructural evidence of thyroid damage in amiodarone-induced thyrotoxicosis

Abstract

Amiodarone-induced thyrotoxicosis occurs in 2-12.1% of patients on chronic amiodarone treatment. In most cases its pathogenesis is related to iodine overload in the presence of preexisting thyroid abnormalities, such as multinodular or diffuse goiter or autonomous nodule. A minority of patients show apparently normal glands or pictures of non-autoimmune thyroiditis. However, there is recent evidence of a direct toxic effect of amiodarone, with consequent release of iodothyronines into the circulation. We report a patient with amiodarone-induced thyrotoxicosis with toxic thyroid effects demonstrated by electron microscopy in a fine-needle aspiration biopsy. There were three main pathologic findings: multilamellar lysosomal inclusions, intramitchondrial glycogen inclusions--both ultrastructural findings indicating thyroid cell damage--and a microscopic morphological pattern of thyroid cell hyperfunction. No inflammatory changes were found. Plasma thyroglobulin levels were high. The patient proved to be a non responder to simultaneous administration of methimazole (starting dose 30 mg/day) and potassium perchlorate (1000 mg/day for 40 days), while still taking amiodarone, thus providing evidence against a possible pathogenetic role of iodine overload. Dexamethasone (starting dose 3 mg/day) was added to methimazole. After three months euthyroidism had been restored and plasma thyroglobulin level substantially decreased. Subsequent subclinical hypothyroidism developed, which persisted after stopping antithyroid treatment and required substitution treatment with levothyroxine. In view of the primary role of lysosome function in the proteolysis of thyroglobulin molecules and of the energy-requiring carrier-mediated transport of monoiodotyrosine across the lysosomal membrane for iodine salvage and reutilization, we suggest that the pathological lysosomal and mitochondrial changes observed could be an ultrastructural marker for subsequent hypothyroidism in amiodarone-induced thyrotoxicosis. Our observations suggest the usefulness of ultrastructural thyroid evaluation and serial plasma thyroglobulin determinations to thoroughly evaluate the underlying pathogenetic mechanisms in amiodarone-associated thyrotoxicosis with apparently normal thyroid glands. Moreover, more knowledge of its pathogenesis could improve both prognostic stratification and treatment guides.

Histopathology of the thyroid in amiodarone‐induced hypothyroidism

“…Cappiello et al . reported a case demonstrating multi‐lamellar lysosomal inclusions, suggesting impairment of lysosome function, along with intramitochondrial glycogen inclusions shown on electron microscopy in fine‐needle aspiration cytology specimen 7 …”

“…Although many clinical case reports on amiodarone‐induced thyroid disorders have been published, little has been reported on the histopathological changes of thyroid tissues in patients with amiodarone‐induced thyroid dysfunction. Only five papers describe the pathological findings in amiodarone‐induced hyperthyroidism 4,7–10 and none in AIH. Histologically, they reported that thyroid tissue from patients with AIH had enlarged and dilated follicles distended by colloid substance, which they regarded as ‘involuted change’, along with follicles infiltrated by macrophages, which they considered to be a ‘destructive or degenerative change’ in the thyroid.…”

Vitamin E Ameliorates the Toxic Effect of Amiodarone on Thyroid Gland in Rats: A Histological and Ultrastructural Study

“…Also, Spaniol et al (2001) stated that amiodarone was a well-known mitochondrial toxin [35] . Cappiello et al (1995) suggested that amiodarone increases the permeability of the mitochondrial membrane with subsequent diffusion of glycogen synthesis enzymes that increase the intramitochondrial glycogen [36] . Also, Zaky and Eid, (2018) clarified that intramitochondrial accumulation of lipid droplets occurred due to inhibition of mitochondrial beta-oxidation by amiodarone therapy [20] .…”

Lithium Toxicity Precipitated by Thyrotoxicosis Due to Silent Thyroiditis: Cardiac Arrest, Quadriplegia, and Coma

“…Several hypotheses have been advanced to explain the mechanism of lithium-associated silent thyroiditis, but at this time, they remain conjectural (22)(23)(24).…”