Monocarboxylate transporter 8 deficiency: Altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy

Abstract

Context: Thyroid hormone transport across the plasma membrane depends on transmembrane transport proteins, including monocarboxylate transporter 8 (MCT8). Mutations in MCT8 (or SLC16A2) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma triiodothyronine (T3) and low/normal thyroxine (T4). MCT8 contributes to hormone release from the thyroid gland. Objective: To characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice. Design: Thyroid morphology in a patient carrying the A224V mutation was followed by ultrasound imaging for over 10 years. After thyroidectomy, a histopathological analysis was carried out. The findings were compared with histological analyses of mouse thyroids from the Mct8-/y model. Results: We show that an inactivating mutation in MCT8 leads to a unique, progressive thyroid follicular pathology in a patient. After thyroidectomy, histological analysis revealed gross morphological changes, including several hyperplastic nodules, microfollicular areas with stromal fibrosis and a small focus of microfollicular structures with nuclear features reminiscent of papillary thyroid carcinoma (PTC). These findings are supported by an Mct8-null mouse model in which we found massive papillary hyperplasia in 6- to 12-month-old mice and nuclear features consistent with PTC in almost 2-year-old animals. After complete thyroidectomy and substitution with levothyroxine (L-T4), the preoperative, inadequately low T 4 and free T4 remained, while increasing the L-T 4 dosage led to T3 serum concentrations above the normal range. Conclusions: Our results implicate peripheral deiodination in the peculiar hormonal constellation of MCT8-deficient patients. Other MCT8-deficient patients should be closely monitored for potential thyroid abnormalities. © 2011 European Society of Endocrinology.