Pharmacodynamic Response to Anti-thyroid Drugs in Graves' Hyperthyroidism

Abstract

Objective: Graves' disease is the commonest cause of hyperthyroidism in populations with sufficient dietary iodine intake. Anti-thyroid drugs (ATD) are often used as the initial treatment for Graves' hyperthyroidism, however there is a paucity of data relating the dose of ATD therapy to the effect on thyroid hormone levels, increasing the risk of both over-and under-treatment. We aimed to determine the pharmacodynamic response to the ATD carbimazole. Design: Retrospective cohort study. Methods: Participants were patients (n = 441) diagnosed with Graves' disease at Imperial College Healthcare NHS Trust between 2009 and 2018. The main outcome measure was change in thyroid hormone levels in response to ATD. Results: Baseline thyroid hormone levels were positively associated with TSH receptor antibody titres (P < 0.0001). Baseline free triiodothyronine (fT3) were linearly related to free thyroxine (fT4) levels in the hyperthyroid state (fT3 = fT4 * 0.97-11), and fell proportionately with carbimazole. The percentage falls in fT4 and fT3 per day were associated with carbimazole dose (P < 0.0001). The magnitude of fall in thyroid hormones after the same dose of carbimazole was lower during follow up than at the initiation visit. The fall in thyroid hormone levels approximated to a linear response if assessed at least 3 weeks after commencement of carbimazole. Following withdrawal of antithyroid drug treatment, the risk of relapse was greater in patients with higher initial fT4, initial TSH receptor antibody titre, males, smokers, and British Caucasian ethnicity. Conclusion: We identify a dose-response relationship for fall in thyroid hormones in response to carbimazole to aid in the selection of dose for Graves' hyperthyroidism.

Treatment of Grave’s Disease in Adults

“…Agranulocytosis due to methimazole predicts the risk of agranulocytosis due to propylthiuracil, therefore the use of propylthiuracil should also be avoided in these patients. Methimazole hepatotoxicity can occur at any dose, is characterized by cholestasis and slowly recovers after discontinuation of the drug [19][20][21].…”

“…The teratogenicity of methimazole occurs by free crossing the placenta, especially in the first trimester, the effects include aplasia cutis, umbilical malformations, facial dysmorphism, esophageal and choanal atresia as well as craniofacial malformations. For this reason, the use of propylthiuracil in the first trimester of pregnancy is preferred [19][20][21].…”

“…The mechanism of action of propylthiuracil is inhibition of thyroid peroxidase, which oxidizes iodine and incorporates it into the tyrosine molecule, preventing the formation of diiodotyrosine and monoiodothyronine. Unlike methimazole, it has a peripheral effect by inhibiting the conversion of T4 to T3 by inhibition of deiodinase [19,20].…”

“…The usual maintenance dose is 100 to 150 mg per day. In patients with thyroid storm the usual dose is 500 to 1000 mg daily divided every 4 hours [19][20][21].…”

“…Hepatic injury is one of the most worrisome adverse effects of the use of propylthiuracil, it occurs frequently in the first 6 months of treatment, however it can occur at any time, the symptoms are specific and the initial diagnosis is made by elevation of liver function markers. Due to the high risk of hepatotoxicity in pregnancy, methimazole is preferred in the second and third trimester of pregnancy [19][20][21].…”