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

• Published in: European journal of endocrinology Vol. 165; no. 4; pp. 555 - 561
• Main Authors: Wirth, Eva K, Sheu, Sien-Yi, Chiu-Ugalde, Jazmin, Sapin, Remy, Klein, Marc O, Mossbrugger, Ilona, Quintanilla-Martinez, Leticia, Hrabě de Angelis, Martin, Krude, Heiko, Riebel, Thomas, Rothe, Karin, Köhrle, Josef, Schmid, Kurt W, Schweizer, Ulrich, Grüters, Annette
• Format: Journal Article
• Language: English
• Published: Bristol BioScientifica 01.10.2011; European Society of Endocrinology
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Carcinoma, Papillary, Follicular - diagnostic imaging; Carcinoma, Papillary, Follicular - pathology; Carcinoma, Papillary, Follicular - surgery; Child; Clinical Study; Electrophoresis, Polyacrylamide Gel; Endocrinopathies; Fundamental and applied biological sciences. Psychology; Humans; Iodide Peroxidase - blood; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocarboxylic Acid Transporters - deficiency; Monocarboxylic Acid Transporters - genetics; Mutation - physiology; Proto-Oncogene Proteins B-raf - genetics; RNA - biosynthesis; RNA - genetics; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgery of endocrine glands; Thyroid Gland - diagnostic imaging; Thyroid Gland - pathology; Thyroid Gland - surgery; Thyroid Neoplasms - diagnostic imaging; Thyroid Neoplasms - pathology; Thyroid Neoplasms - surgery; Thyroidectomy; Thyroxine - blood; Treatment Outcome; Triiodothyronine - blood; Ultrasonography; Vertebrates: endocrinology; Endocrine gland; Treatment; Surgery; Deficiency; Morphology; Thyroxine; Thyroid hormone; Ratio; Thyroid gland; Triiodothyronine; Thyroidectomy; Endocrinology
• ISSN: 0804-4643; 1479-683X
• DOI: 10.1530/EJE-11-0369

ContextThyroid 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.ObjectiveTo characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice.DesignThyroid 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.ResultsWe 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 T4 and free T4 remained, while increasing the l-T4 dosage led to T3 serum concentrations above the normal range.ConclusionsOur 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.