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Amiodarone
Amiodarone is the most complex and difficult of the drugs that can affect thyroid status (table 2) (Wiersinga, 1996, Harjai &Licata, 1997). A benign form of euthyroid hyperthyroxinemia, with high total and free T4, normal or subnormal serum T3 and increased serum rT3 occurs in up to one third of amiodarone-treated subjects (fig 5). This abnormality requires no treatment - the diagnosis of amiodarone-induced thyrotoxicosis should not be based on T4 excess alone. Figure 5:
In iodine-replete regions the predominant important amiodarone-induced thyroid abnormality is hypothyroidism which is especially likely to occur when there is a background of thyroid autoimmunity. Routine replacement with T4 is effective, but therapy may need to be modified because of the underlying heart disease, or because of the effects of amiodarone to decrease T4 clearance and to increase serum TSH. The most troublesome and important abnormalities that result from amiodarone therapy are two unpredictable forms of thyrotoxicosis, one due to iodine excess, the other attributed to a unique form of persistent thyroiditis (Harjai & Licata, 1997) in which unusual intracellular inclusion bodies have been identified (Smyrk et al, 1987). The latter condition can occur rapidly, without any premonitory abnormality of thyroid function and can be life-threatening. Weight loss, deterioration of cardiac function and severe myopathy are often the predominant clinical features. A distinction between these two forms of amiodarone-induced thyrotoxicosis by colour Doppler flow studies has been reported (Bogazzi et al, 1997). If blood flow is increased (type 1), the thyrotoxicosis may be directly due to iodine excess; conventional antithyroid drugs, with the possible addition of potassium perchlorate, may be appropriate first-line therapy. In the type 2 variant attributed to thyroiditis which shows markedly decreased blood flow, high dose glucocorticoids may be beneficial. It should be noted that the therapeutic value of this distinction has not yet been conclusively proven. There can be poor correlation between circulating thyroid hormone levels and the clinical manifestations of amiodarone-induced thyrotoxicosis, perhaps because of interaction of this drug, or its active metabolite desethylamiodarone, with T3 receptors (Wiersinga, 1996). TSH levels generally tend to be higher, for the same level of free T4 and free T3, when amiodarone-treated subjects are compared with T4-treated subjects (fig 1). Lithium This agent which has become widely used in the management of manic-depressive illness, has multiple effects on the pituitary-thyroid axis, the most important being an effect to inhibit thyroglobulin hydrolysis and hormone release (Lazarus, 1996). Its effects to inhibit iodide uptake and thyroid hormone synthesis are probably of lesser importance. As well as affecting thyroid hormone release, lithium exacerbates autoimmune thyroid disease of the Hashimoto type, often causing smooth, symmetrical gland enlargement followed eventually by primary hypothyroidism. Women with positive anti-peroxidase antibodies are especially likely to develop this form of goitrous hypothyroidism. In a recent retrospective study of over 690 lithium-treated Scottish patients, 14% of women and 4.5% of men developed various grades of primary hypothyroidism. (Johnston & Eagles, 1999). There are also reports of lithium-induced thyrotoxicosis, of probable autoimmune origin (Lazarus, 1996). Serum TSH, T4 and T3 assays generally give a true index of thyroid status during lithium treatment, although concurrent use of carbamazepine may give spuriously low values for serum free T4 in assays that use diluted serum (see above). It is generally recommended that the thyroid should be examined, and that TSH, free T4 and anti-peroxidase antibodies be assessed before commencement of lithium therapy, with serial evaluation of thyroid status every 6-12 months during treatment, or if a goitre develops. Thyroxine replacement is recommended if there is TSH excess or progressive thyroid enlargement, even if TSH remains within the reference range. Doses of T4 sufficient to suppress TSH to subnormal or undetectable levels probably result in more effective goitre regression, but this point remains unproven. Phenytoin The antiepileptic phenytoin commonly results in subnormal serum total T4 , with an apparent lowering of free T4, not accompanied by the anticipated increase in TSH (Surks & Defesi, 1996). Such findings, which are not easily distinguishable from central hypothyroidism due to pituitary deficiency, have been attributed to the possible action of phenytoin as a partial thyroid hormone agonist (Smith&Surks, 1984). In addition to this effect, phenytoin displaces T4 from TBG, but, as outlined above, the increase in free T4 fraction is poorly reflected by assay methods that use diluted samples (Surks & Defesi, 1996). Using standard assay methods, these effects together result in a TSH-free T4 relationship in serum that can be identical to that seen in secondary hypothyroidism, although it is generally agreed that patients taking longterm phenytoin are euthyroid. It remains uncertain how an accurate assessment of thyroid status can be made in hypopituitary patients who are taking T4 together with phenytoin or carbamazepine. Phenytoin accelerates T4 clearance by induction of cytochrome P450 enzymes, so that the replacement dose may need to be increased in the treatment of hypothyroidism. Treatment with phenytoin or carbamazepine can make previously optimal treatment of primary hypothyroidism inadequate, or may unmask diminished thyroid reserve (Blackshear et al, 1983). |
