Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Eur J Endocrinol. 2011 Oct;165(4):555-61. doi: 10.1530/EJE-11-0369. Epub 2011 Aug 3.
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 (T(3)) and low/normal thyroxine (T(4)). MCT8 contributes to hormone release from the thyroid gland.
To characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice.
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.
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-T(4)), the preoperative, inadequately low T(4) and free T(4) remained, while increasing the l-T(4) dosage led to T(3) serum concentrations above the normal range.
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.
甲状腺激素穿过质膜的转运依赖于跨膜转运蛋白，包括单羧酸转运蛋白 8（MCT8）。MCT8（或 SLC16A2）的突变导致一种严重的 X 连锁精神运动发育迟缓，其特征是血浆三碘甲状腺原氨酸（T3）升高和甲状腺素（T4）低/正常。MCT8 有助于甲状腺激素从甲状腺中的释放。
在患者和 Mct8 缺陷小鼠中研究 MCT8 缺乏对甲状腺形态的潜在影响。
对携带 A224V 突变的患者进行甲状腺超声成像超过 10 年，并进行了组织病理学分析。将结果与 Mct8(-/y)模型的小鼠甲状腺组织学分析进行了比较。
我们发现 MCT8 中的失活突变导致患者出现独特的、进行性的甲状腺滤泡病理学改变。甲状腺切除术后，组织学分析显示出明显的形态学变化，包括多个增生性结节、间质纤维化的微滤泡区和一小部分具有核特征类似于甲状腺乳头状癌（PTC）的微滤泡结构。这些发现得到了 Mct8 缺失小鼠模型的支持，在该模型中，我们发现 6-12 月龄的小鼠存在大量的乳头状增生，2 岁左右的动物几乎存在符合 PTC 的核特征。在进行完全甲状腺切除术并用左甲状腺素（l-T4）替代后，术前过低的 T4 和游离 T4 仍然存在，而增加 l-T4 剂量会导致 T3 血清浓度超过正常范围。
我们的结果表明外周脱碘作用参与了 MCT8 缺乏患者独特的激素失调。其他 MCT8 缺乏患者应密切监测潜在的甲状腺异常。
