Atypical variants of graves' disease: Pathogenesis, phenotypic expression and challenges in management

Abstract

Graves’ disease is the commonest cause of primary hyperthyroidism. Although the clinical presentation is typical and management routine in most cases, there are some uncommon but distinct presentations which are important for primary care physicians to recognize, in terms of both diagnosis and management. Triiodothyroninine (T3)-predominant Graves’ disease is characterized by persistently elevated serum T3 levels associated with normal or low serum thyroxine (T4) levels during therapy with thionamides. Graves’ disease in this form is much more aggressive and is resistant to medical and radioactive iodine (I-131) treatment, requiring surgery in most cases. The pathogenetic mechanisms, possible reasons for resistance to medical treatment and management of this form of Graves’ thyrotoxicosis are discussed. Low pool-high iodine (substrate) turnover Graves’ disease is another unique presentation of Graves’ disease. In such cases, serum free T3 and free T4 decline precipitously with low doses of anti-thyroid drugs and yet escalate acutely on downtitration or discontinuation of the drug. The possible pathogenetic mechanisms for the marked fluctuations in thyroid hormones to small thionamide doses or dose adjustments, and the merits of different anti-thyroid drug regimens in these cases, are explored. Cyclical Graves’ disease, wherein TSH receptor antibodies switch from predominantly stimulatory to blocking types at different time intervals, manifests with fluctuations of serum T4 and T3 levels that result in periodic alternating hyperthyroidism and hypothyroidism. The patient may experience hypothyroid symptoms at one time point and hyperthyroid symptoms at another time. We discuss the possible pathogenetic mechanisms and management options in this variant of Graves’ disease.